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Lai J, Hu D, Yan M, Chen Q, Shi H, Yang Q, Ding M, Li L, Zhang H, Bai L. A novel off-liver sinusoidal progenitor cells in supporting transplantable bioliver engineering. BIOMATERIALS ADVANCES 2025; 176:214358. [PMID: 40435930 DOI: 10.1016/j.bioadv.2025.214358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/18/2025] [Accepted: 05/22/2025] [Indexed: 06/16/2025]
Abstract
Liver transplantation is the only curative option for liver failure, which is currently limited by organ shortages. Although liver tissue engineering (LTE) with a strategy of decellularization/recellularization opens a new window to overcome this limitation, its challenges include the lack of specific seed cell sources and appropriate methods to support recellularization. In this preliminary study, both in vitro and in vivo experiments were performed. In vitro, we used novel off-liver progenitors of liver sinusoidal endothelial cells (LSECs) isolated from bone marrow mesenchymal stem cells (NG2/BMMSCs) and a method to establish transplantable biolivers in an advanced decellularized liver scaffold (rDLS). This partial liver scaffolds (rDLS) shows advantages over whole liver scaffolds (nDLS) and also maintains both microvascular network and naturally regenerative microenvironmental niche, enhancing effective recellularization of the NG2/BMMSCs compared to nDLS in reconstructing hepatic main architectures of endothelial, sinusoidal and biliary tree before seeding hepatic stem cells (MLpvNG2 and ratOv cells). The recellularized hepatic stem cells-mediated bioliver was subsequently induced in a 3D bioreactor-like system with three different conditioned media (CM1-CM3) for different culture durations. Importantly, the NG2/BMMSC-lined rDLSs effectively supported the functional bioliver engineering. In vivo, compared with control recipient pigs that underwent ∼90 % hepatectomy only, the recipients subjected to the same hepatectomy and received the bioliver presented greater survival durations. Overall, this study presents a new technology for fabricating a NG2/BMMSC-based transplantable bioliver that may become a promising treatment for liver failure.
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Affiliation(s)
- Jiejuan Lai
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, PR China
| | - Deyu Hu
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, PR China; Bioengineering College, Chongqing University, No. 175 Gaotan, ShapingBa District, Chongqing 400044, PR China
| | - Min Yan
- Department of Special Medicine, Shanxi Medical University, Taiyuan 030000, PR China
| | - Quanyu Chen
- Hepatobiliary Institute, Southwest Hospital, Army Medical University, No. 30 Gaotanyan, ShapingBa District, Chongqing 400038, PR China
| | - Hongbo Shi
- Translational Hepatology Institute, Beijing Municipal Key Laboratory, Capital Medical University, No.8 Xitoutiao, Youwai Street, Fengtai District, Beijing 100069, PR China
| | - Qi Yang
- Translational Hepatology Institute, Beijing Municipal Key Laboratory, Capital Medical University, No.8 Xitoutiao, Youwai Street, Fengtai District, Beijing 100069, PR China
| | - Mei Ding
- Translational Hepatology Institute, Beijing Municipal Key Laboratory, Capital Medical University, No.8 Xitoutiao, Youwai Street, Fengtai District, Beijing 100069, PR China
| | - Lu Li
- Translational Hepatology Institute, Beijing Municipal Key Laboratory, Capital Medical University, No.8 Xitoutiao, Youwai Street, Fengtai District, Beijing 100069, PR China
| | - Hongyu Zhang
- Department of Hepatobiliary Surgery, HYGEIA International Hospital, Chongqing 401331, PR China
| | - Lianhua Bai
- Translational Hepatology Institute, Beijing Municipal Key Laboratory, Capital Medical University, No.8 Xitoutiao, Youwai Street, Fengtai District, Beijing 100069, PR China.
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Ma N, Yip R, Woodward M, Lewis S, Crane M, Jirapatnakul A, Aloman C, Bansal MB, Dieterich D, Gros L, Valvi D, Colicino E, Yankelevitz D, Henschke C, Branch AD. Mixture analysis of associations between environmental and workplace toxins and liver damage and telomere length, stratified by race/ethnicity. J Environ Sci (China) 2025; 155:316-328. [PMID: 40246468 PMCID: PMC12006726 DOI: 10.1016/j.jes.2024.08.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 08/07/2024] [Accepted: 08/17/2024] [Indexed: 04/19/2025]
Abstract
This study aimed to identify the worst "bad actors" in mixtures of pollutants contributing to liver damage and shorter telomeres in the U.S. population, using weighted quantile sum (WQS) modeling with stratification by race/ethnicity. We conducted a comprehensive cross-sectional analysis of mixtures of pollutants in National Health and Nutrition Examination Survey datasets: (1) 33,979 adults with blood levels of cadmium (Cd), lead (Pb), and mercury, including subsets with measurements of per-/polyfluoroalkyl substances (PFAS), and polychlorinated biphenyls (PCBs)/polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs); and (2) 7360 adults with measurements of telomeres, Cd, and Pb. Multivariable-adjusted WQS regression examined associations between WQS mixture indices and liver injury (alanine aminotransferase (ALT)-elevation), advanced liver-fibrosis (LF), and telomere length. WQSmetal indices were associated with advanced-LF in all racial/ethnic groups. The top contributor was Cd in the total population and in non-Hispanic Whites (NHW), while Pb was the top contributor in non-Hispanic Blacks (NHB). The WQSmetal-PCB-PCDD/F index was associated with ALT-elevation, with PCB126, Cd and Pb as main contributors; the odds ratio (OR) per decile was 1.50 (95 % CI, 1.26-1.78), while the OR per decile of the WQSmetal-PFAS index was 1.03 (95 % CI, 0.98-1.05), not significant. WQSmetal indices were associated with shorter telomeres. Cd was main contributor associated with advanced-LF in NHW, while Pb was the major bad actor in NHB, suggesting that NHB may be especially susceptible to Pb toxicity. Metals were associated with shorter telomeres. Metal and PCB/PCDD/F mixtures were associated with ALT-elevation. Heavy metals and organic chemicals may contribute to liver-related morbidity and healthcare disparities.
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Affiliation(s)
- Ning Ma
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Rowena Yip
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Mark Woodward
- The George Institute for Global Health, School of Public Health, Imperial College London, London, W12 7RZ, UK; The George Institute for Global Health, University of New South Wales, Sydney, 2000, Australia
| | - Sara Lewis
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Michael Crane
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Artit Jirapatnakul
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Costica Aloman
- Department of Medicine, Division of Gastroenterology and Hepatobiliary Diseases, Westchester Medical Center, Valhalla, 10595, USA
| | - Meena B Bansal
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Douglas Dieterich
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Louis Gros
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Damaskini Valvi
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Elena Colicino
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - David Yankelevitz
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Claudia Henschke
- Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Andrea D Branch
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Abdlaty R, Abbass MA, Awadallah AM. Toward near real-time precise supervision of radiofrequency ablation for liver fibrosis using hyperspectral imaging. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 336:125994. [PMID: 40086137 DOI: 10.1016/j.saa.2025.125994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 02/17/2025] [Accepted: 03/04/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND AND AIMS Chronic liver diseases pose a significant global health concern, ranking as the 11th leading cause of death worldwide. It often progresses to organ fibrosis and severe complications such as portal hypertension and cirrhosis. Liver transplantation is the most effective treatment for such diseases, however, the persistent shortage of donors highlights the need for alternatives. Radiofrequency ablation (RFA) is a promising alternative since it is a minimally invasive procedure. RFA uses heat to destroy abnormal tissues. Its benefits include reduced recovery time compared to surgery, precise targeting of affected areas, and long-lasting symptom relief in many cases. However, RFA has challenges, such as potential risks of nerve damage, infection, or incomplete ablation, requiring repeat treatments. Although significant progress in RFA techniques, effective monitoring remains challenging due to the limited ability to accurately characterize the dynamic thermal diffusion and complex tissue responses. METHODS To address this challenge, hyperspectral imaging (HSI) shows promise in monitoring tissue necrosis post-ablation. Our study evaluated HSI's efficacy in monitoring RFA on ex vivo human fibrotic liver tissue samples. RESULTS Statistical analysis revealed correlations between spectral patterns and tissue conditions, which helped identify the optimal spectral bands of 543 nm and 579 nm for accurately distinguishing different tissue states. Analyzing the hemoglobin absorption profile indicated significant reductions in absorption of the green light band, showing approximately 40 % reduction in fibrotic tissue and around 20 % reduction in ablated tissue when compared to normal liver tissue. Additionally, a threshold was established for predicting the ablated area of liver samples, ensuring a condition of 90 % specificity. CONCLUSIONS Consequently, HSI proved to be a valuable tool for monitoring ablation and a step for improving treatment outcomes for liver fibrosis.
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Affiliation(s)
- Ramy Abdlaty
- Department of Biomedical Engineering, Military Technical College, Cairo, Egypt.
| | - Mohamed A Abbass
- Department of Biomedical Engineering, Military Technical College, Cairo, Egypt
| | - Ahmed M Awadallah
- Department of Biomedical Engineering, Military Technical College, Cairo, Egypt
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Wang Z, Li Y, Wang X, Zhang W, Chen Y, Lu X, Jin C, Tu L, Jiang T, Yang Y, Ma X, Zeng J, Wen Y, Efferth T. Precision Strike Strategy for Liver Diseases Trilogy with Xiao-Chai-Hu Decoction: A Meta-Analysis with Machine Learning. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156796. [PMID: 40347886 DOI: 10.1016/j.phymed.2025.156796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 03/30/2025] [Accepted: 04/20/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND AND PURPOSE The progression from hepatitis to liver fibrosis (LF) and ultimately to hepatic carcinoma (HCC) represents the advanced stages of various liver diseases. Currently, no universal treatment effectively addresses all three conditions. The Traditional Chinese Medicine formula Xiao-Chai-Hu decoction (XCHD) has shown promise in treating hepatitis, inhibiting LF, and serving as an adjunct therapy for HCC. This study evaluates the efficacy and optimal treatment durations of XCHD in managing these liver diseases using meta-analysis and machine learning techniques. METHODS Registered in the PROSPERO database (CRD42024534445), this meta-analysis systematically searched seven databases, including 54 studies with a total of 5,710 patients. Statistical analysis was performed using Stata 17.0. Five machine learning models-Random Forest (RF), XGBoost, Lasso, Multilayer Perceptron (MLP), and a stacking model combining these algorithms-were employed to analyze the data and predict the time-effect relationships. The optimal durations of XCHD treatment for the liver disease trilogy were subsequently projected. RESULTS XCHD significantly improved the primary outcome indicators for hepatitis, liver fibrosis, and HCC. Additionally, XCHD demonstrated a beneficial effect on liver dysfunction caused by these diseases. Machine learning predicted the optimal treatment durations of XCHD as 12 weeks for hepatitis, 20.31 weeks for liver fibrosis, and 12 weeks for HCC. CONCLUSION XCHD is effective in treating the liver disease trilogy, with optimal treatment durations of 12 weeks for hepatitis and HCC, and 20.31 weeks for liver fibrosis. These findings support the potential of XCHD in developing precise clinical strategies for managing liver diseases. This study innovatively integrates meta-analysis with machine learning to determine the optimal treatment durations, providing a novel approach for evidence-based precision medicine in Traditional Chinese Medicine.
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Affiliation(s)
- Zexin Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yubing Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaobao Wang
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaohua Lu
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Chunmei Jin
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Lang Tu
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Tao Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiqin Yang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
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Zhang J, Chen X, Chai Y, Jin Y, Li F, Zhuo C, Xu Y, Wang H, Ju E, Lao YH, Xie X, Li M, Tao Y. Mesenchymal stromal/stem cell spheroid-derived extracellular vesicles advance the therapeutic efficacy of 3D-printed vascularized artificial liver lobules in liver failure treatment. Bioact Mater 2025; 49:121-139. [PMID: 40124595 PMCID: PMC11930233 DOI: 10.1016/j.bioactmat.2025.02.042] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 02/25/2025] [Accepted: 02/25/2025] [Indexed: 03/25/2025] Open
Abstract
Acute liver failure (ALF) is a highly lethal condition characterized by massive tissue necrosis, excessive oxidative stress, and serious inflammatory storms, necessitating prompt medical intervention. Although hepatocyte-like cells (HLCs) derived from mesenchymal stromal/stem cells (MSCs) offer a promising alternative cell source for hepatocyte therapy, their low in-vivo integration and differentiation efficiency may compromise the eventual therapeutic efficacy. To this end, MSCs are bioengineered into multicellular spheroids in the present study. The proteomic analyses and experimental results reveal that extracellular vesicles (EVs) derived from these MSC spheroids (SpEV) contain abundant highly expressed bioactive proteins and can be efficiently endocytosed by recipient cells, resulting in enhanced pro-angiogenic and antioxidative effects. In addition, MSC spheroids exhibit superior hepatic cell differentiation compared to an equivalent number of dissociated single MSCs, particularly when being co-cultured with hexagonally patterned endothelial cells in a liver lobule-like arrangement. Following orthotopic implantation in the mouse model, the enhanced paracrine effects of SpEV, combined with an immunoregulatory decellularized extracellular matrix hydrogel carrier and functional artificial liver lobules (ALL), synergically contribute to the effective amelioration of ALF, highlighting the substantial potential for clinical translation.
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Affiliation(s)
- Jiabin Zhang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Xiaodie Chen
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yurong Chai
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yuanyuan Jin
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Fenfang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Chenya Zhuo
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yanteng Xu
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Enguo Ju
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yeh-Hsing Lao
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA
| | - Xi Xie
- State Key Laboratory of Optoelectronic Materials and Technologies, Guangdong Province Key Laboratory of Display Material and Technology, School of Electronics and Information Technology, Sun Yat-sen University, Guangzhou, 510006, China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-Sen University, Guangzhou, 510275, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China
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Saeed K, Chughtai MFJ, Ahsan S, Mehmood T, Khalid MZ, Khaliq A, Zuhair M, Khalid W, Alsulami T, Law D, Mukonzo EL. Hepatoprotective Effect of a Kalanchoe pinnata-Based Beverage Against Carbon Tetrachloride- and Gentamicin-Induced Hepatotoxicity in Wistar Rats. JOURNAL OF THE AMERICAN NUTRITION ASSOCIATION 2025; 44:405-421. [PMID: 39937610 DOI: 10.1080/27697061.2024.2442615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 12/08/2024] [Accepted: 12/11/2024] [Indexed: 02/14/2025]
Abstract
OBJECTIVE Chronic liver diseases are accountable for approximately 2 million deaths annually. The current study aimed to test the putative prophylactic role of Kalanchoe pinnata against hepatic stress. METHOD Kalanchoe pinnata leaf extracts utilized in beverage production were obtained via 3 different extraction techniques (conventional solvent extraction, supercritical fluid extraction, microwave-assisted extraction). RESULTS The highest values on 2,2-diphenyl-1-picrylhydrazyl, ferric reducing antioxidant power, and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid assay were from a beverage prepared with supercritical fluid extract. When the prophylactic aspects of a Kalanchoe pinnata-based beverage were explored against carbon tetrachloride- (CCl4-) and gentamicin-induced hepatotoxic conditions in male Wistar rats, results revealed a reduction in serum aspartate aminotransferase, serum alkaline phosphatase, serum alanine transaminase, and bilirubin levels in rats with CCl4 and gentamicin-induced toxicity. The study also concluded that the administration of a therapeutic beverage significantly improved serum total protein, albumin, and globulin levels in Kalanchoe pinnata-treated rats. CONCLUSIONS Our findings support the ameliorative potential of Kalanchoe pinnata against liver diseases.
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Affiliation(s)
- Kanza Saeed
- Institute of Food Science and Technology, Faculty of Food Health Science and Technology, Khwaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan
- Faculty of Food Technology and Nutrition Sciences, University of Biological and Applied Sciences, Lahore, Pakistan
| | - Muhammad Farhan Jahangir Chughtai
- Institute of Food Science and Technology, Faculty of Food Health Science and Technology, Khwaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan
| | - Samreen Ahsan
- Institute of Food Science and Technology, Faculty of Food Health Science and Technology, Khwaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan
| | - Tariq Mehmood
- Institute of Food Science and Technology, Faculty of Food Health Science and Technology, Khwaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan
| | - Muhammad Zubair Khalid
- Department of Food Science, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan
| | - Adnan Khaliq
- Institute of Food Science and Technology, Faculty of Food Health Science and Technology, Khwaja Fareed University of Engineering and Information Technology, Rahim Yar Khan, Pakistan
| | - Muhammad Zuhair
- National Institute of Food Science and Technology, University of Agriculture, Faisalabad, Pakistan
| | - Waseem Khalid
- Department of Organic Chemistry, Faculty of Chemical Sciences and Technologies, University of Castilla La Mancha, Ciudad Real, Spain
| | - Tawfiq Alsulami
- Department of Food Science & Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi Arabi
| | - Douglas Law
- Faculty of Health and Life Sciences, INTI International University, Nilai, Malaysia
| | - Emery Lenge Mukonzo
- Land Evaluation and Agro-metrology Research Unit, Department of Soil Science, Faculty of Agriculture Research, University of Lubumbashi, Lubumbashi, DR Congo
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Ali R, Li H, Zhang H, Pan W, Reeder SB, Harris D, Masch W, Aslam A, Shanbhogue K, Bernieh A, Ranganathan S, Parikh N, Dillman JR, He L. Multi-site, multi-vendor development and validation of a deep learning model for liver stiffness prediction using abdominal biparametric MRI. Eur Radiol 2025; 35:4362-4373. [PMID: 39779515 DOI: 10.1007/s00330-024-11312-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 11/04/2024] [Accepted: 11/24/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Chronic liver disease (CLD) is a substantial cause of morbidity and mortality worldwide. Liver stiffness, as measured by MR elastography (MRE), is well-accepted as a surrogate marker of liver fibrosis. PURPOSE To develop and validate deep learning (DL) models for predicting MRE-derived liver stiffness using routine clinical non-contrast abdominal T1-weighted (T1w) and T2-weighted (T2w) data from multiple institutions/system manufacturers in pediatric and adult patients. MATERIALS AND METHODS We identified pediatric and adult patients with known or suspected CLD from four institutions, who underwent clinical MRI with MRE from 2011 to 2022. We used T1w and T2w data to train DL models for liver stiffness classification. Patients were categorized into two groups for binary classification using liver stiffness thresholds (≥ 2.5 kPa, ≥ 3.0 kPa, ≥ 3.5 kPa, ≥ 4 kPa, or ≥ 5 kPa), reflecting various degrees of liver stiffening. RESULTS We identified 4695 MRI examinations from 4295 patients (mean ± SD age, 47.6 ± 18.7 years; 428 (10.0%) pediatric; 2159 males [50.2%]). With a primary liver stiffness threshold of 3.0 kPa, our model correctly classified patients into no/minimal (< 3.0 kPa) vs moderate/severe (≥ 3.0 kPa) liver stiffness with AUROCs of 0.83 (95% CI: 0.82, 0.84) in our internal multi-site cross-validation (CV) experiment, 0.82 (95% CI: 0.80, 0.84) in our temporal hold-out validation experiment, and 0.79 (95% CI: 0.75, 0.81) in our external leave-one-site-out CV experiment. The developed model is publicly available ( https://github.com/almahdir1/Multi-channel-DeepLiverNet2.0.git ). CONCLUSION Our DL models exhibited reasonable diagnostic performance for categorical classification of liver stiffness on a large diverse dataset using T1w and T2w MRI data. KEY POINTS Question Can DL models accurately predict liver stiffness using routine clinical biparametric MRI in pediatric and adult patients with CLD? Findings DeepLiverNet2.0 used biparametric MRI data to classify liver stiffness, achieving AUROCs of 0.83, 0.82, and 0.79 for multi-site CV, hold-out validation, and external CV. Clinical relevance Our DeepLiverNet2.0 AI model can categorically classify the severity of liver stiffening using anatomic biparametric MR images in children and young adults. Model refinements and incorporation of clinical features may decrease the need for MRE.
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Affiliation(s)
- Redha Ali
- Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Hailong Li
- Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Neurodevelopmental Disorders Prevention Center, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Artificial Intelligence Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Huixian Zhang
- Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Wen Pan
- Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Scott B Reeder
- Department of Radiology, University of Wisconsin, Madison, WI, USA
- Department of Medical Physics, Biomedical Engineering, Medicine, Emergency Medicine, University of Wisconsin, Madison, WI, USA
| | - David Harris
- Department of Radiology, University of Wisconsin, Madison, WI, USA
| | - William Masch
- Department of Radiology, Michigan Medicine, Ann Arbor, MI, USA
| | - Anum Aslam
- Department of Radiology, Michigan Medicine, Ann Arbor, MI, USA
| | | | - Anas Bernieh
- Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | | | - Nehal Parikh
- Neurodevelopmental Disorders Prevention Center, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jonathan R Dillman
- Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Artificial Intelligence Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
| | - Lili He
- Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Neurodevelopmental Disorders Prevention Center, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Artificial Intelligence Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Department of Computer Science, Biomedical Engineering, Biomedical Informatics, University of Cincinnati, Cincinnati, OH, USA.
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Nasr G, Ali DME, Fawzy MA, Ali FEM, Fathy M. Combined quercetin with phosphodiesterase inhibitors; sildenafil and pentoxifylline alleviated CCl 4-induced chronic hepatic fibrosis: Role of redox-sensitive pathways. Food Chem Toxicol 2025; 201:115442. [PMID: 40220882 DOI: 10.1016/j.fct.2025.115442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 04/02/2025] [Accepted: 04/09/2025] [Indexed: 04/14/2025]
Abstract
Liver fibrosis is a common pathological condition that is caused by complicated molecular and cellular processes. This study evaluated the therapeutic potential of combined quercetin (QU) with either sildenafil (Sild) or pentoxifylline (PTX) in chronic carbon tetrachloride (CCl4)-induced liver fibrosis in Wistar albino rats. Fibrosis was induced by CCl4 injections (1.5 mg/kg, i.p.) three times weekly for 10 weeks. After six weeks, rats received oral QU (50 mg/kg/day), Sild (50 mg/kg/day), or PTX (10 mg/kg twice/day) individually or in combination for the remaining four weeks. Results showed significant alterations in liver biochemical markers, histopathology, oxidative stress, inflammation, apoptosis, and hypoxic responses due to CCl4 exposure. These changes included reduced expression of Nrf-2, HO-1, and cytoglobin, alongside increased levels of NF-κB, cleaved caspase-3, TNF-α, IL-1β, and HIF-1. Notably, QU, Sild, and PTX, individually or in combination, improved these parameters. The combination of QU with Sild or PTX proved more effective than single treatments, modulating anti-oxidant (Nrf2/HO-1/cytoglobin), anti-inflammatory (NF-κB/TNF-α), and hypoxic signaling pathways (HIF-1α). In conclusion, QU combined with phosphodiesterase inhibitors shows promise as a therapy for liver fibrosis, offering enhanced protection through anti-oxidants and anti-inflammatory mechanisms.
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Affiliation(s)
- Gehad Nasr
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag, 82524, Egypt
| | | | - Michael A Fawzy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
| | - Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba, 77110, Jordan.
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt; Biochemistry Department, Faculty of Pharmacy, Minia National University, New Minia, Egypt
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9
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Li J, Qin M, Tang Y, Dan J, Chen H, Chen H, Huang J, Yang Y, Wang T, Li Y, Chen M, Ju W, Wang D, Guo Z, Tan H, He X, Zhao Q. Simplified ischemia-free liver transplantation by providing alternating flow of the portal vein and hepatic artery: Applicability, efficiency, and safety. Liver Transpl 2025; 31:737-749. [PMID: 39641582 DOI: 10.1097/lvt.0000000000000545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Accepted: 11/15/2024] [Indexed: 12/07/2024]
Abstract
Conventional ischemia-free liver transplantation (CIFLT) represents a pioneering procedure that circumvents ischemia-reperfusion injury to livers throughout the transplant procedure. However, its complexity has limited its widespread adoption. This study introduced a simplified ischemia-free liver transplantation (SIFLT) technique by providing an alternating flow of the portal vein and hepatic artery, demonstrating its efficacy and safety. In this retrospective study, 32 patients who received SIFLT and 32 who received CIFLT were included between January 2021 and January 2024. The intraoperative and postoperative outcomes were collected and elevated. Patients who underwent SIFLT had a shorter anhepatic phase (44.0±2.4 vs. 51.6±2.4 min, p =0.03), along with a comparatively reduced intraoperative blood loss compared to those who underwent CIFLT. Furthermore, the SIFLT group exhibited significantly lower peak AST levels within postoperative 7 days (413.1±62.6 vs. 707.5±110.7 U/L, p =0.02). The incidence of early allograft dysfunction, primary nonfunction, and transplant-related complications were similar across both groups. There were no significant differences in the number of Clavien-Dindo classification of surgical complications and comprehensive complication index at 3 months after transplantation. Kaplan-Meier analysis confirmed similar patient and graft survival rates. The subgroup analysis of extended criteria donor demonstrated that SIFLT can effectively reduce anhepatic phase and intraoperative blood loss and can achieve a clinical prognosis similar to CIFLT. Additionally, histological analysis revealed that both groups demonstrated well-preserved livers and bile ducts. The SIFLT simplifies the intricate surgical procedure while ensuring the protection of livers from ischemia-reperfusion injury. This technique holds promise for enabling patients to achieve clinical outcomes comparable to those of CIFLT.
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Affiliation(s)
- Jiahao Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Meiting Qin
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yunhua Tang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Jia Dan
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Honghui Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Huadi Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Jinbo Huang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yongqi Yang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Tielong Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Yefu Li
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Maogen Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Weiqiang Ju
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Dongping Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Haidong Tan
- Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
| | - Qiang Zhao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China
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Jin H, Liang Z, Hu X, Li X, Liu Z, Qiao Y, Cheng Y, Yao H, Liu Y. Comparative association of MAFLD/MASLD and Subtypes with Cardiovascular Diseases Outcomes. Nutr Metab Cardiovasc Dis 2025; 35:104024. [PMID: 40189471 DOI: 10.1016/j.numecd.2025.104024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/04/2025] [Accepted: 03/18/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND AND AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) acts as an alternative for demarcating metabolic dysfunction-associated fatty liver disease (MAFLD). This study aimed to investigate the factors that significantly influence the relationship between MAFLD and MASLD in relation to the incidence of major cardiovascular outcomes. METHODS AND RESULTS A total of 340,998 participants in the UK Biobank study were included. Multivariable Cox proportional hazards models were used to estimate the effect of MAFLD and MASLD on the outcomes of cardiovascular diseases (CVDs) (coronary artery disease, stroke, heart failure, and CVD-related death) with hazard ratios (HRs) and 95 % confidence intervals (CIs). A total of 126,077 (36.97 %) participants had MAFLD and 97,418 (28.57 %) had MASLD. Over a median follow-up of 13.5 years (interquartile range 12.6-14.2), there were 41,548 new events of CVDs recorded. MAFLD (HR = 1.52; 95 % CI: 1.49-1.55) and MASLD (HR = 1.42; 95 % CI: 1.39-1.45) were associated with high risks of CVDs. Among the subtypes of MAFLD and steatotic liver disease (SLD), MAFLD diabetes subtype (HR = 2.26; 95 % CI: 2.17-2.35) and alcohol-associated liver disease (ALD) (HR = 1.65; 95 % CI: 1.55-1.76) exhibited the highest risk of CVDs. MAFLD overweight without MD subtype were not associated with CVDs. The effect of MAFLD on the CVD outcomes was consistent regardless of the presence of MASLD. CONCLUSION The metabolic health status and alcohol consumption function as more critical factors than obesity in assessing CVD outcomes in participants with MAFLD or MASLD.
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Affiliation(s)
- Huizhen Jin
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University, Changchun, 130021, China
| | - Zhuoshuai Liang
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University, Changchun, 130021, China
| | - Xinmeng Hu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University, Changchun, 130021, China
| | - Xiaoyang Li
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University, Changchun, 130021, China
| | - Zhantong Liu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University, Changchun, 130021, China
| | - Yichun Qiao
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University, Changchun, 130021, China
| | - Yi Cheng
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China
| | - Hanxin Yao
- Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Yawen Liu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University, Changchun, 130021, China; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, School of Public Health, Jilin University, Changchun, 130062, China.
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11
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Sadri M, Shafaghat Z, Roozbehani M, Hoseinzadeh A, Mohammadi F, Arab FL, Minaeian S, Fard SR, Faraji F. Effects of Probiotics on Liver Diseases: Current In Vitro and In Vivo Studies. Probiotics Antimicrob Proteins 2025; 17:1688-1710. [PMID: 39739162 DOI: 10.1007/s12602-024-10431-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2024] [Indexed: 01/02/2025]
Abstract
Various types of liver or hepatic diseases cause the death of about 2 million people worldwide every year, of which 1 million die from the complications of cirrhosis and another million from hepatocellular carcinoma and viral hepatitis. Currently, the second most common solid organ transplant is the liver, and the current rate represents less than 10% of global transplant requests. Hence, finding new approaches to treat and prevent liver diseases is essential. In liver diseases, the interaction between the liver, gut, and immune system is crucial, and probiotics positively affect the human microbiota. Probiotics are a non-toxic and biosafe alternative to synthetic chemical compounds. Health promotion by lowering cholesterol levels, stimulating host immunity, the natural gut microbiota, and other functions are some of the activities of probiotics, and their metabolites, including bacteriocins, can exert antimicrobial effects against a broad range of pathogenic bacteria. The present review discusses the available data on the results of preclinical and clinical studies on the effects of probiotic administration on different types of liver diseases.
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Affiliation(s)
- Maryam Sadri
- Department of Immunology, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Shafaghat
- Department of Immunology, Iran University of Medical Sciences, Tehran, Iran
| | - Mona Roozbehani
- Vaccine Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Akram Hoseinzadeh
- Cancer Research Center, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Fatemeh Mohammadi
- Department of Immunology, School of Medicine, Mashhad University of Medicine Sciences, Mashhad, Iran
| | - Fahimeh Lavi Arab
- Department of Immunology, School of Medicine, Mashhad University of Medicine Sciences, Mashhad, Iran
| | - Sara Minaeian
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medicine Sciences, Tehran, Iran
| | - Soheil Rahmani Fard
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medicine Sciences, Tehran, Iran
| | - Fatemeh Faraji
- Antimicrobial Resistance Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medicine Sciences, Tehran, Iran.
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12
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Novokhodko A, Hao S, Ahmad S, Gao D. Non-Cell-Based Extracorporeal Artificial Liver Systems: Historic Perspectives, Approaches and Mechanisms, Current Applications, and Challenges. Artif Organs 2025; 49:925-944. [PMID: 39737603 DOI: 10.1111/aor.14931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 11/03/2024] [Accepted: 12/09/2024] [Indexed: 01/01/2025]
Abstract
BACKGROUND Liver disease is a growing burden. Transplant organs are scarce. Extracorporeal liver support systems (ELSS) are a bridge to transplantation for eligible patients. For transplant-ineligible patients the objective becomes liver recovery. METHODS We review seven decades of non-cell-based ELSS research in humans. Where possible, we emphasize randomized controlled trials (RCTs). When RCTs are not available, we describe the available human clinical data. RESULTS There are three broad cell-free approaches to remove protein-bound toxins (PBTs) and treat liver failure. The first is a dialysate binder suspension. A material that binds the PBT (the binder) is added to the dialysate. Binders include albumin, charcoal, and polystyrene sulfonate sodium. The unbound fraction of the PBT crosses the dialyzer membrane along a chemical gradient and binds to the binder. The second approach is using grains of sorbent fixed in a plastic housing to remove PBTs. Toxin-laden blood or plasma flows directly through the column. Toxins are removed by binding to the sorbent. The third approach is exchanging toxin-laden blood, or fractions of blood, for a healthy donor blood product. Most systems lack widespread acceptance, but plasma exchange (PE) is recommended in many guidelines. The large donor plasma requirement of PE creates demand for systems to complement or replace it. CONCLUSIONS Now that PE has become recommended in some, but not all, jurisdictions, we discuss the importance of reporting precise PE protocols and dose. Our work provides an overview of promising new systems and lessons from old technologies to enable ELSS improvement.
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Affiliation(s)
- Alexander Novokhodko
- Department of Mechanical Engineering, University of Washington, Seattle, Washington, USA
| | - Shaohang Hao
- Department of Mechanical Engineering, University of Washington, Seattle, Washington, USA
| | - Suhail Ahmad
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Dayong Gao
- Department of Mechanical Engineering, University of Washington, Seattle, Washington, USA
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13
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Mohamed RS, Akl EM, Dacrory S. Fabrication of sodium alginate/polyvinyl alcohol@ ZnNPs with SPI scaffold for evaluation of immune-stimulating and liver-protective effects in methotrexate-treated rats. Int J Biol Macromol 2025; 311:143514. [PMID: 40286953 DOI: 10.1016/j.ijbiomac.2025.143514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 04/10/2025] [Accepted: 04/24/2025] [Indexed: 04/29/2025]
Abstract
Fabrication of new 3D scaffold based on sodium alginate (SA), polyvinyl alcohol (PVA), sesame protein isolate (SPI) and Zinc nanoparticles (ZnNPs) has been prepared. SPI was extracted and evaluated via its amino acid composition, solubility, and antioxidant activity. The scaffolds were formulated with different ratios of SA/PVA/Zn/SPI and investigated via different instruments FTIR, XRD and SEM/EDX. Additionally, the effect of the scaffold on the hepato-protection and immune-stimulating in methotrexate (MTX) treated rats has been studied. The results showed that SPI rich in Arginine (21.33 %), Histidine (15 %), Aspartic acid (12.7 %) and Glutamic acid (9.69 %). SPI exhibited higher solubility and antioxidant activity at pH 7 (47.55 and 87.23 %) when measured by DPPH and ABTS methods respectively. SPI and Zn have the ability to mitigate the effects of MTX on body weight loss. SA/PVA/ZnNPs and SA/PVA/ZnNPs/SPI scaffolds have potential liver protection by down-regulating liver functions (34.83 ± 1.17 U/L and 27.83 ± 1.08 U/L, respectively for ALT and 53.00 ± 1.15 U/L and 48.29 ± 1.29 U/L, respectively for AST) and oxidative and inflammatory markers (MDA, IL-6, IL-1β, and TNF-α) and up-regulating liver antioxidant enzymes (GPx and SOD). Furthermore, the immune-enhancing effects of SA/PVA/ZnNPs and SA/PVA/ZnNPs/SPI scaffolds were demonstrated by the reduction in INF-γ (33.17 ± 0.94 pg/mL and 27.73 ± 0.68 pg/mL, respectively) and CD8 (381.5 ± 2.56 pg/mL and 337.8 ± 1.87 pg/mL, respectively) levels and the elevation in CD4/CD8 ratio (1.79 ± 0.02 and 3.00 ± 0.01, respectively) comparable to the MTX group (41.25 ± 0.85 pg/mL, 531.7 ± 2.56 pg/mL and 0.99 ± 0.005, respectively). Thus, the scaffold may have a role in liver protection and immune enhancement.
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Affiliation(s)
- Rasha S Mohamed
- Nutrition and Food Sciences Department, National Research Centre, Cairo, Egypt
| | - Engy M Akl
- Fats and Oils Department, National Research Centre, Cairo, Egypt.
| | - Sawsan Dacrory
- Cellulose & Paper Department, National Research Centre, Giza, Egypt.
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14
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Ma L, Wang W, Gu L, Wang L. cPLA 2α on the influence of Th17 and its role in the formation of liver fibrosis. Cytotechnology 2025; 77:87. [PMID: 40206205 PMCID: PMC11977053 DOI: 10.1007/s10616-025-00750-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/29/2025] [Indexed: 04/11/2025] Open
Abstract
This study primarily investigated the mechanism and pathways of the cPLA2α signaling pathway on Th17-mediated HSC activation and liver fibrosis, providing insights for clinical strategies to target HSC activation and delay the rapid progression of liver fibrosis. In vitro and in vivo model were established, and different concentrations of the cPLA2α inhibitor AACOCF3 were administered respectively for intervention. The expression of IL- 17 was detected by ELISA, and the expression of cPLA2α protein and HSC activation protein α-SMA index were detected by Western blot and immunofluorescence. In addition, observe the changes in the degree of liver fibrosis in mice through the pathological staining of mouse livers. In an in vitro system, Th17 could induce HSC activation. And after intervention, the results showed that the inhibitor could inhibit Th17 activation of HSC. Next, in an in vivo model, Th17 could also induce HSC activation. And after intervention, the results showed that the inhibitor could also inhibit HSC activation by Th17. Observation under liver pathological staining showed that the inflammation and staining were significantly reduced in the intervention group, suggesting a therapeutic effect of AACOCF3. Using in vitro and in vivo approaches, these data suggest that Th17 cells can promote the activation and proliferation of HSCs, which further exerts a role in promoting liver fibrosis. These data also suggest that the cPLA2α pathway may be involved in the activation of HSCs by Th17 cells and induce liver fibrosis mechanisms.
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Affiliation(s)
- Lina Ma
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, 250014 Shandong China
- Shandong First Medical University, Jinan, 250117 Shandong China
| | - Wei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, 250014 Shandong China
- Shandong First Medical University, Jinan, 250117 Shandong China
| | - Limin Gu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, 250014 Shandong China
- Shandong First Medical University, Jinan, 250117 Shandong China
| | - Liyun Wang
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, 250014 Shandong China
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15
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Zhang S, Han P, Sun H, Su Y, Chen C, Chen C, Li J, Lv X, Tian X, Xu Y. Discovery of Active Ingredient of Yinchenhao Decoction Targeting TLR4 for Hepatic Inflammatory Diseases Based on Deep Learning Approach. Interdiscip Sci 2025; 17:293-305. [PMID: 39560852 DOI: 10.1007/s12539-024-00670-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 10/22/2024] [Indexed: 11/20/2024]
Abstract
Yinchenhao Decoction (YCHD), a classic formula in traditional Chinese medicine, is believed to have the potential to treat liver diseases by modulating the Toll-like receptor 4 (TLR4) target. Therefore, a thorough exploration of the effective components and therapeutic mechanisms targeting TLR4 in YCHD is a promising strategy for liver diseases. In this study, the AIGO-DTI deep learning framework was proposed to predict the targeting probability of major components in YCHD for TLR4. Comparative evaluations with four machine learning models (RF, SVM, KNN, XGBoost) and two deep learning models (GCN, GAT) demonstrated that the AIGO-DTI framework exhibited the best overall performance, with Recall and AUC reaching 0.968 and 0.991, respectively.This study further utilized the AIGO-DTI model to identify the potential impact of Isoscopoletin, a major component of YCHD, on TLR4. Subsequent wet experiments revealed that Isoscopoletin could influence the maturation of Dendritic Cells (DCs) induced by Lipopolysaccharide (LPS) through TLR4, suggesting its therapeutic potential for liver diseases, especially hepatitis. Additionally, based on the AIGO-DTI framework, this study established an online platform named TLR4-Predict to facilitate domain experts in discovering more compounds related to TLR4. Overall, the proposed AIGO-DTI framework accurately predicts unique compounds in YCHD that interact with TLR4, providing new insights for identifying and screening lead compounds targeting TLR4.
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Affiliation(s)
- Sizhe Zhang
- College of Software, Xinjiang University, Urumqi, 830046, China
| | - Peng Han
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830017, China
| | - Haiqing Sun
- College of Software, Xinjiang University, Urumqi, 830046, China
| | - Ying Su
- College of Information Science and Engineering, Xinjiang University, Urumqi, 830046, China
| | - Chen Chen
- College of Information Science and Engineering, Xinjiang University, Urumqi, 830046, China
| | - Cheng Chen
- College of Software, Xinjiang University, Urumqi, 830046, China
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, 830017, China
| | - Xiaoyi Lv
- College of Software, Xinjiang University, Urumqi, 830046, China.
| | - Xuecong Tian
- College of Information Science and Engineering, Xinjiang University, Urumqi, 830046, China.
| | - Yandan Xu
- Quzhou Kecheng People' S Hospital, Quzhou, 324000, China.
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16
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Zhu H, Wang G, Liao Z, Zhang W. AITL-Net: An adaptive interpretable transfer learning network with robust generalization for liver cancer recognition. Knowl Based Syst 2025; 318:113473. [DOI: 10.1016/j.knosys.2025.113473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
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17
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Li R, Tai Y, Zhang X, Liu Z, Si H, Kong D, Zhao L, Li J, Midgley AC. Tissue-Microenvironment-Responsive Self-Assembling Peptide Nanoshells Boost Pirfenidone Efficacy in the Treatment of Liver Fibrosis. Adv Healthc Mater 2025; 14:e2500101. [PMID: 40331409 DOI: 10.1002/adhm.202500101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Indexed: 05/08/2025]
Abstract
Chronic liver disease culminates in liver fibrosis, responsible for substantial worldwide morbidity and mortality. Traditional chemical drugs that have proven effective at treating other types of tissue fibrosis may be repurposed for treating liver fibrosis but face inefficient outcomes or elicit undesirable side effects. Hepatic-targeted drug nanocarriers offer a potential strategy for achieving localized drug release to effectively alleviate liver fibrosis while mitigating off-target effects. Elevated levels of fibroblast activation protein-α (FAP-α) have been associated with liver fibrosis and the presence of platelet-derived growth-factor-receptor-β-overexpressing activated hepatic stellate cells. Therefore, FAP-α-responsive nanoshells are developed from hepatic fibrosis targeting peptides to protect and transport pirfenidone (PFD) to fibrotic livers for potentiated therapeutic efficacy. In vitro experiments validate that PFD-loaded hepatic- and fibrosis-targeting nanoshells (PFD@ns) lessen transforming-growth-factor-β1-driven collagen production and activation of hepatic stellate cells. In animal models of liver fibrosis, PFD@ns increase the efficacy of PFD in preventing fibrosis, alleviating proinflammatory cell infiltration, and modulating the PI3K/AKT/mTOR signaling pathway. In conclusion, these findings suggest that the hepatic- and fibrosis-targeted PFD@ns can potentially serve as an effective tool in the treatment of liver fibrosis.
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Affiliation(s)
- Ruifang Li
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yifan Tai
- Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Xinyan Zhang
- Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Zhen Liu
- Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Haipeng Si
- Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Deling Kong
- Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Lili Zhao
- Department of Gastroenterology and Hepatology, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Jia Li
- School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Gastroenterology and Hepatology, Tianjin Second People's Hospital, Tianjin, 300192, China
| | - Adam C Midgley
- Key Laboratory of Bioactive Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
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Olofson A, Lennon R, Kassmeyer B, Liu K, Attia ZI, Rushlow D, Rattan P, Ahn JC, Friedman PA, Allen A, Kamath PS, Shah VH, Noseworthy PA, Simonetto DA. Detection of Undiagnosed Liver Cirrhosis via Artificial Intelligence-Enabled Electrocardiogram (DULCE): Rationale and design of a pragmatic cluster randomized clinical trial. Contemp Clin Trials Commun 2025; 45:101494. [PMID: 40491662 PMCID: PMC12148367 DOI: 10.1016/j.conctc.2025.101494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 04/11/2025] [Accepted: 05/16/2025] [Indexed: 06/11/2025] Open
Abstract
Background Cirrhosis is a leading cause of morbidity and mortality worldwide, yet preventable at early stages. Currently, effective approaches for early diagnosis are lacking. A novel electrocardiogram (ECG)-enabled deep learning model trained for detection of advanced chronic liver disease (CLD) has demonstrated promising results and it may be used for screening of advanced CLD in primary care. Design A pragmatic, cluster randomized trial (NCT05782283) in 45 Mayo Clinic primary care practices will be conducted over a period of 6 months with 6 months of follow up. Care teams will be randomized 1:1 to intervention or usual care, stratified by region and patient volume. Patients from providers enrolled in the trial who undergo an ECG during the study period will be included. In the intervention arm, consenting providers to patients identified as higher risk of advanced CLD based on their ECG will be notified with a recommendation for noninvasive fibrosis assessment. The primary endpoint will be detection of advanced CLD (defined as stage 3-4 on blood- or imaging-based noninvasive liver disease assessment or liver biopsy). Secondary outcomes will include completion of fibrosis assessment tests within 180 days of ECG, new diagnosis of liver disease stratified by etiology and risk factors for CLD, and detection of any liver fibrosis (stages 1-4). Post-study surveys to participating clinicians will be conducted. Summary Preliminary findings suggest outstanding potential for the use of an ECG-enabled machine learning algorithm for detection of advanced CLD in the primary care community.
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Affiliation(s)
- Amy Olofson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Ryan Lennon
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Blake Kassmeyer
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Kan Liu
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Zacchi I. Attia
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - David Rushlow
- Department of Family Medicine, Mayo Clinic, Rochester, MN, USA
| | - Puru Rattan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Joseph C. Ahn
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Paul A. Friedman
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
| | - Alina Allen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Patrick S. Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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19
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Zhao Y, Bo Y, Zu J, Xing Z, Yang Z, Zhang Y, Deng Y, Liu Y, Zhang L, Yuan X, Wang Y, Henry L, Ji F, Nguyen MH. Global Burden of Chronic Liver Disease and Temporal Trends: A Population-Based Analysis From 1990 to 2021 With Projections to 2050. Liver Int 2025; 45:e70155. [PMID: 40421876 DOI: 10.1111/liv.70155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 04/30/2025] [Accepted: 05/19/2025] [Indexed: 05/28/2025]
Abstract
BACKGROUND AND AIMS Globally, the aetiology and epidemiology of chronic liver disease (CLD) are undergoing significant changes. We aimed to investigate the updated global burden of CLD, evaluate the cross-country inequalities, and provide 2050 predictions. METHODS Using the Global Burden of Disease Study (GBD) 2021 data resources, we analysed and forecasted CLD prevalence, incidence, and related death from 1990-2021 to 2050, respectively. We calculated average annual percent change (AAPC) by joinpoint regression model and quantified inequalities according to World Health Organisation-recommended health equity standards. RESULTS In 2021, the number of prevalent, incident CLD and related deaths globally were 1.7 billion (95% uncertainty interval (UI): 1.6-1.8), 58.4 million (95% UI: 54.2-62.8) and 1.4 million (95% UI: 1.3-1.5), respectively. During 1990-2021, the age-standardised incidence rate (ASIR) increased, especially in those aged 15-49 (AAPC: 0.49%; 95% confidence interval [CI]: 0.45%-0.53%), in Europe (AAPC: 0.41%; 95% CI: 0.41%-0.42%) and the Americas (AAPC: 0.41%; 95% CI: 0.39%-0.42%), whereas the age-standardised death rate (ASDR) decreased globally (AAPC: -1.26%; 95% CI: -1.35% [-1.17%]) and across subgroups. During 1990-2021, the ASIR of metabolic dysfunction-associated steatotic liver disease (MASLD) increased the most in those aged 15-49 (AAPC: 0.72%; 95% CI: 0.67%-0.77%) and in the Western Pacific region (AAPC: 0.73%; 95% CI: 0.59%-0.86%). Socio-demographic index (SDI)-related inequalities decreased for the age-standardised prevalence rate (ASPR) and ASIR of CLD but increased for ASDR, placing a disproportionately heavier burden on low-SDI countries. From 2022 to 2050, the ASIR of CLD is projected to increase (AAPC: 0.20%; 95% CI: 0.19%-0.20%), but the ASDR is projected to decline (AAPC: -1.91%; 95% CI: -1.96% [-1.85%]). CONCLUSIONS This study's findings highlight targeted interventions for CLD disparities, focusing on MASLD management, the younger population (15-49 years), and socio-demographic inequalities.
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Affiliation(s)
- Yunyu Zhao
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yajing Bo
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jian Zu
- School of Mathematics and Statistics, Xi'an Jiaotong University, Xi'an, China
| | - Zixuan Xing
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhanpeng Yang
- School of Mathematics and Statistics, Xi'an Jiaotong University, Xi'an, China
| | - Yue Zhang
- School of Mathematics and Statistics, Xi'an Jiaotong University, Xi'an, China
| | - Yujiao Deng
- Division of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yi Liu
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lanting Zhang
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiao Yuan
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuan Wang
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Linda Henry
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
| | - Fanpu Ji
- Department of Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi, China
- Key Laboratory of Surgical Critical Care and Life Support (Xi'an Jiaotong University), Ministry of Education of China, Xi'an, Shaanxi, China
- Global Health Institute, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, China
- Shaanxi Provincial Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA
- Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA
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20
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Ge T, Wang Y, Han Y, Bao X, Lu C. Exploring the Updated Roles of Ferroptosis in Liver Diseases: Mechanisms, Regulators, and Therapeutic Implications. Cell Biochem Biophys 2025; 83:1445-1464. [PMID: 39543068 DOI: 10.1007/s12013-024-01611-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2024] [Indexed: 11/17/2024]
Abstract
Ferroptosis, a newly discovered mode of cell death, is a type of iron-dependent regulated cell death characterized by intracellular excessive lipid peroxidation and imbalanced redox. As the liver is susceptible to oxidative damage and the abnormal iron accumulation is a major feature of most liver diseases, studies on ferroptosis in the field of liver diseases are of great interest. Studies show that targeting the key regulators of ferroptosis can effectively alleviate or even reverse the deterioration process of liver diseases. System Xc- and glutathione peroxidase 4 are the main defense regulators of ferroptosis, while acyl-CoA synthetase long chain family member 4 is a key enzyme causing peroxidation in ferroptosis. Generally speaking, ferroptosis should be suppressed in alcoholic liver disease, non-alcoholic fatty liver disease, and drug-induced liver injury, while it should be induced in liver fibrosis and hepatocellular carcinoma. In this review, we summarize the main regulators involved in ferroptosis and then the mechanisms of ferroptosis in different liver diseases. Treatment options of drugs targeting ferroptosis are further concluded. Determining different triggers of ferroptosis can clarify the mechanism of ferroptosis occurs at both physiological and pathological levels.
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Affiliation(s)
- Ting Ge
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yang Wang
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yiwen Han
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Xiaofeng Bao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Chunfeng Lu
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
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21
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Hou Y, Lv B, Du J, Ye M, Jin H, Yi Y, Huang Y. Sulfide regulation and catabolism in health and disease. Signal Transduct Target Ther 2025; 10:174. [PMID: 40442106 PMCID: PMC12122839 DOI: 10.1038/s41392-025-02231-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/03/2025] [Accepted: 03/21/2025] [Indexed: 06/02/2025] Open
Abstract
The metabolic pathway of sulfur-containing amino acids in organisms begins with methionine, which is metabolized to produce important sulfur-containing biomolecules such as adenosylmethionine, adenosylhomocysteine, homocysteine, cystine, and hydrogen sulfide (H2S). These sulfur-containing biomolecules play a wide range of physiological roles in the body, including anti-inflammation, antioxidant stress, DNA methylation, protein synthesis, etc., which are essential for maintaining cellular function and overall health. In contrast, dysregulation of the metabolic pathway of sulfur-containing amino acids leads to abnormal levels of sulfur-containing biomolecules, which produce a range of pathological consequences in multiple systems of the body, such as neurodegenerative diseases, cardiovascular diseases, and cancer. This review traces the milestones in the development of these sulfur-containing biomolecules from their initial discovery to their clinical applications and describes in detail the structure, physiochemical properties, metabolism, sulfide signaling pathway, physiopathological functions, and assays of sulfur-containing biomolecules. In addition, the paper also explores the regulatory role and mechanism of sulfur-containing biomolecules on cardiovascular diseases, liver diseases, neurological diseases, metabolic diseases and tumors. The focus is placed on donors of sulfur-containing biological macromolecule metabolites, small-molecule drug screening targeting H2S-producing enzymes, and the latest advancements in preclinical and clinical research related to hydrogen sulfide, including clinical trials and FDA-approved drugs. Additionally, an overview of future research directions in this field is provided. The aim is to enhance the understanding of the complex physiological and pathological roles of sulfur-containing biomolecules and to offer insights into developing effective therapeutic strategies for diseases associated with dysregulated sulfur-containing amino acid metabolism.
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Affiliation(s)
- Yuanyuan Hou
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, 100034, China
| | - Boyang Lv
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, 100034, China
| | - Junbao Du
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, 100034, China
| | - Min Ye
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China
- Yunnan Baiyao International Medical Research Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Hongfang Jin
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, 100034, China.
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China.
| | - Yang Yi
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
- Yunnan Baiyao International Medical Research Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
| | - Yaqian Huang
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, 100034, China.
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22
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Skladaný Ľ, Líška D, Mesiková K, Havaj D, Adamcová-Selčanová S, Šulejová K, Žilinčanová D, Kohout P. Does the change in Liver Frailty Index over the first week of hospitalisation predict mortality in patients with acute-on-chronic liver failure? A prospective cohort study from a Slovak liver centre. BMJ Open 2025; 15:e100171. [PMID: 40441763 PMCID: PMC12121596 DOI: 10.1136/bmjopen-2025-100171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 05/09/2025] [Indexed: 06/02/2025] Open
Abstract
OBJECTIVE Hospital admissions for advanced chronic liver disease (ACLD) are associated with increased mortality, disability, a decline in quality of life and significant economic costs. Being admitted to the hospital usually indicates a triggering event that disrupted a previously stable condition, leading to decompensation or complications of ACLD. The most acute and severe manifestation of this imbalance is acute-on-chronic liver failure (ACLF), a syndrome representing a critical juncture. Reliable prognostic stratification of patients admitted with ACLF could facilitate the systematic delivery of tailored care, ranging from palliative care to intensive interventions like extracorporeal liver support devices and prioritised liver transplantation. Disease-specific prognostic tools, such as the Model for End-Stage Liver Disease score, are effective but have limitations, particularly in reflecting a patient's potential for recovery. The concept of the body's functional reserve in the context of ACLD/ACLF is gaining attention, with the Liver Frailty Index (LFI) potentially emerging as a recommended diagnostic tool. METHODS Patients were selected from our cirrhosis registry (RH7). The LFI serves as an indicator of the patient's prognosis. The LFI measurement takes place at two time intervals: on the patient's admission and after 7 days of hospitalisation. RESULTS Our RH7 registry included 154 patients (15.1%) who were diagnosed with ACLF. The primary cause of the underlying ACLD was alcohol-associated liver disease in the majority (79.8%) of cases. The mean value of LFI at admission was 4.50 (± 0.94). When patients with liver cirrhosis were categorised into three subgroups based on the LFI on day 7, survival exhibited a statistically significant decrease (p≤0.05) across all three ACLF grades. This decline in survival was observed from the 'improved LFI' cohort, through the 'stable LFI' group, to the 'worsened LFI' group. CONCLUSION The impact of day 7 LFI on the survival of patients with ACLF is notable. Nevertheless, it does not markedly enhance the predictive capability of the LFI assessed on admission. Consequently, the initial LFI on day 1 continues to be the most valuable and commonly used instrument for promptly recognising individuals with ACLF.
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Affiliation(s)
- Ľubomír Skladaný
- Department of Hepatology, Gastroenterology, and Transplantation, 2nd Department of Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Banska Bystrica, Slovakia
| | - Dávid Líška
- Faculty of Sport Science and Health, Matej Bel University, Banska Bystrica, Slovakia
| | - Klaudia Mesiková
- F.D. Roosevelt University Hospital of Banská Bystrica, Banská Bystrica, Slovakia
| | - Daniel Havaj
- Department of Hepatology, Gastroenterology, and Transplantation, 2nd Department of Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Banska Bystrica, Slovakia
| | - Sveltana Adamcová-Selčanová
- Department of Hepatology, Gastroenterology, and Transplantation, 2nd Department of Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Banska Bystrica, Slovakia
| | - Karolína Šulejová
- Department of Hepatology, Gastroenterology, and Transplantation, 2nd Department of Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Banska Bystrica, Slovakia
| | - Daniela Žilinčanová
- Department of Hepatology, Gastroenterology, and Transplantation, 2nd Department of Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Banska Bystrica, Slovakia
| | - Pavel Kohout
- Department of Internal Medicine, Third Faculty of Medicine, Charles University Prague and Teaching Thomayer Hospital, Prague, Czech Republic
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23
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Wang Z, Qu Q, Jiang R, Li Z, Ran S. The association between chronic liver disease and osteoporosis in East Asian populations: a bidirectional Mendelian randomization study. Aging Clin Exp Res 2025; 37:168. [PMID: 40415161 DOI: 10.1007/s40520-025-03031-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 03/24/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND Chronic liver disease is a widespread health problem globally, particularly common in East Asia. Osteoporosis (OP), as a common metabolic bone disease, has also gained increasing attention in aging societies. In recent years, studies have suggested a possible association between chronic liver disease and OP, but their causal relationship has not been fully or systematically studied. OBJECTIVE To investigate the causal association between chronic liver disease and OP in East Asian populations using Mendelian randomization (MR) methods. METHODS The datasets for chronic hepatitis B infection (CHB), chronic hepatitis C infection (CHC), and cirrhosis were sourced from the UK Biobank, while those for hepatocellular carcinoma (HCC) and OP were from the Japan Biobank. All participants included were from East Asian populations. We first treated chronic liver disease as the exposure and OP as the outcome for MR analysis, and then performed a reverse analysis treating OP as the exposure and chronic liver disease as the outcome. The inverse variance-weighted (IVW) method was used as the primary method to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). MR-Egger and the weighted median method were used as supplementary approaches to assess the causal association between chronic liver disease and OP. Heterogeneity and pleiotropy tests were also performed to ensure the reliability of the results. RESULTS The IVW method results indicated that CHB (ebi-a-GCST90018584) will increase the incidence of OP (bbj-a-137) (OR = 1.063, 95% CI: 1.015-1.112, p = 0.009), with no evidence of heterogeneity or pleiotropy. However, no causal association was found between CHC, cirrhosis, or HCC on OP. Reverse MR analyses did not reveal any significant causal effect of OP on chronic liver disease. CONCLUSION In East Asian populations, CHB will increase the incidence of OP. Therefore, CHB patients not only require long-term antiviral treatment to protect the liver but should also monitor their bone health over time to reduce the risk of OP, ultimately improving quality of life.
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Affiliation(s)
- Zhiyu Wang
- Medical College, Hubei Minzu University, 39 Xueyuan Road, Enshi, 445000, China
- Huanggang Hospital of Traditional Chinese Medicine Affiliated with Hubei University of Chinese Medicine, 19 Dongmen Road, Huanggang, 438000, China
| | - Qi Qu
- Medical College, Hubei Minzu University, 39 Xueyuan Road, Enshi, 445000, China
- Huanggang Hospital of Traditional Chinese Medicine Affiliated with Hubei University of Chinese Medicine, 19 Dongmen Road, Huanggang, 438000, China
| | - Rui Jiang
- Huanggang Hospital of Traditional Chinese Medicine Affiliated with Hubei University of Chinese Medicine, 19 Dongmen Road, Huanggang, 438000, China
- Hubei University of Traditional Chinese Medicine, 16 Huangjiahu West Road, Wuhan, 430065, China
| | - Zhongshan Li
- Huanggang Hospital of Traditional Chinese Medicine Affiliated with Hubei University of Chinese Medicine, 19 Dongmen Road, Huanggang, 438000, China.
- Hubei University of Traditional Chinese Medicine, 16 Huangjiahu West Road, Wuhan, 430065, China.
| | - Simiao Ran
- Medical College, Hubei Minzu University, 39 Xueyuan Road, Enshi, 445000, China.
- Huanggang Hospital of Traditional Chinese Medicine Affiliated with Hubei University of Chinese Medicine, 19 Dongmen Road, Huanggang, 438000, China.
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24
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Ye RQ, Chen YF, Ma C, Cheng X, Guo W, Li S. Advances in identifying risk factors of metabolic dysfunction-associated alcohol-related liver disease. Biomed Pharmacother 2025; 188:118191. [PMID: 40408808 DOI: 10.1016/j.biopha.2025.118191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 05/13/2025] [Accepted: 05/21/2025] [Indexed: 05/25/2025] Open
Abstract
Metabolic dysfunction-associated alcohol-related liver disease (MetALD) is an emerging clinical entity that reflects the coexistence of metabolic dysfunction and alcohol-related liver injury. Unlike classical alcoholic liver disease (ALD), MetALD patients often present with lower to moderate alcohol consumption alongside metabolic risk factors such as obesity, insulin resistance, and dyslipidemia. These factors can synergistically worsen liver injury even at lower alcohol intake levels. Alcohol abuse remains a major global health concern, with the liver being the primary target of alcohol's toxic effects. Long-term alcohol exposure, especially when compounded by metabolic dysfunction, can accelerate the progression from steatosis to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Besides alcohol itself, various factors, including genetic predispositions, gender, type of alcoholic beverage, drinking patterns, and co-morbidities such as viral infections (HBV, HCV) modulate disease susceptibility and severity. This review summarizes current knowledge of risk factors contributing to MetALD, highlights the synergistic interactions between metabolic dysfunction and alcohol consumption, and discusses potential strategies for disease prevention and management.
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Affiliation(s)
- Rui-Qi Ye
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China; Xinhua Clinical Medical College, Shanghai Jiao Tong University, Shanghai 200135, China
| | - Yi-Fan Chen
- College of Basic Medical Sciences, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Chang Ma
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xi Cheng
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wei Guo
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
| | - Sha Li
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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25
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Wang R, Ma F, Yin D, Wang H, Wei X. Intestinal Microbes, Metabolites, and Hormones in Alcohol-Associated Liver Disease. Semin Liver Dis 2025. [PMID: 40334703 DOI: 10.1055/a-2601-9480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Alcohol-associated liver disease (ALD)-encompassing conditions including steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma-refers to hepatic damage arising from excessive or hazardous alcohol consumption, and is now recognized as a significant global health burden. Although the mechanisms underlying ALD remain incompletely understood, several pathways have been substantiated over the last five decades, notably the involvement of intestinal microorganisms and the involvement of the gut-liver axis in alcohol metabolism and ALD pathogenesis. Ethanol intake disrupts the intestinal microbial balance and compromises the gut barrier, resulting in increased permeability to microbial products. The subsequent translocation of microbial metabolites and other antigenic substances to the liver activates hepatic immune responses, thereby contributing to liver injury. In addition, gastrointestinal hormones are also implicated in ALD progression through various mechanisms. Although no therapies for ALD have been approved by the Food and Drug Administration, various therapeutic strategies targeting the intestinal microbiota and gut barrier have been identified. In conclusion, this review discusses the role of the gut-liver axis in alcohol metabolism and ALD pathogenesis and explores the emerging therapeutic strategies.
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Affiliation(s)
- Ruimeng Wang
- Second Clinical Medical College, Anhui Medical University, Hefei, China
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Fang Ma
- Center for Scientific Research of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Dou Yin
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiaohui Wei
- Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
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Song J, Zhang H, Zhang X, Liu M, Peng D, Ren Y, Sun Y, Li Y. Galactose-modified erythrocyte membrane fusion liposomes enable the targeted delivery of drug nanoparticles to the liver. RSC Adv 2025; 15:17781-17794. [PMID: 40443690 PMCID: PMC12120831 DOI: 10.1039/d4ra07489k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 04/11/2025] [Indexed: 06/02/2025] Open
Abstract
The safe and efficient delivery of chemicals and biologics remains crucial for liver disease therapy. In this study, we developed a targeted drug delivery system utilizing a galactose-modified erythrocyte membrane coating technique and drug liposome nanoparticles, which were further optimized using orthogonal experiments and response surface analysis. The specificity, precision, accuracy, and stability exhibited satisfactory performance in bioanalytical analysis. Specifically, targeting ligands (Gal-DSPE-PEG3400) were efficiently inserted into red blood cell (RBC) membranes using a facile insertion method. When Gal-DSPE-PEG3400-RBC was fused with fenofibrate liposome nanoparticles (FNB-Lip) by co-extrusion, the resulting galactose-modified erythrocyte membrane fusion liposome nanoparticles (Gal-RBC-FNB-Lip) showed long-term stability, excellent biocompatibility, prolonged retention time, and superior liver accumulation and therapeutic efficacy. These qualities make it suitable for effective drug delivery. The findings of this study will provide a fundamental basis for research and development of liver-targeted drugs and offer novel insights into the treatment of clinical liver diseases.
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Affiliation(s)
- Jiayu Song
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
- College of Medical Technology, Luohe Medical College Luohe 462000 P. R. China
| | - Huanhuan Zhang
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Xiaohui Zhang
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Meiying Liu
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Dan Peng
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Yuan Ren
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Yan Sun
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
| | - Yunlan Li
- School of Public Health, Shaanxi University of Chinese Medicine Xi'an 712046 P. R. China
- School of Pharmaceutical Science, Shanxi Medical University Taiyuan 030001 P. R. China +86 13111066649
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Rashdan HRM, Hassan S, Maher S, Okasha H. Towards novel liver injury therapies based on design, synthesis and therapeutic efficacy of novel sulfone bis-compound on liver necrosis. Sci Rep 2025; 15:17546. [PMID: 40394185 PMCID: PMC12092813 DOI: 10.1038/s41598-025-02483-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 05/13/2025] [Indexed: 05/22/2025] Open
Abstract
Liver necrosis is the irreversible loss of hepatocytes through toxin-induced injury, ischemia, or infection to produce organ dysfunction. It is a significant pathological marker in many liver disorders, including cirrhosis, and hepatitis, and contributes to organ failure and general systemic effects. This research aims to evaluate the protective effects of a newly synthesized compound named 1-(5-((1-(1-(4-((4-(4-(1-((5-acetyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)ethyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)sulfonyl)phenyl)-5-methyl-1H-1,2,3-triazol-4-yl)ethylidene)hydrazono)-4-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl)ethan-1-one (TTTE) sulfone-bis chalcone derivative on liver necrosis caused by TAA therapy using murine model. The research investigates optimal cellular pathways which demonstrate the therapeutic properties of TTTE as a potential treatment for liver injuries. The newly prepared compound TTTE was successfully characterized by Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (1H-NMR) spectroscopy, carbon-13 nuclear magnetic resonance (13C-NMR), The safety of the as-prepared compound TTTE was determined based on weight changes and the behaviors in all the groups were monitored for 21 days. The effect of treatment of TTTE at different doses (300, 200, and 100 mg/kg B.W.) was studied. High-dose TTTE revealed a 62.5% survival rate compared to the untreated TAA group (40%). Molecular analysis exhibited that high-dose TTTE downregulated Cas-3, TIMP-1, and proinflammatory cytokines (TNF-α, NF-κB, and IL-6) compared to untreated TAA. Results of histopathological and IHC examinations exhibited high TTTE dose have no signs of liver injury with suppression in TGF-β expression as a result of anti-inflammatory response. Our study concluded that the synthesized compound, TTTE has a potential therapeutic strategy in mitigating liver necrosis.
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Affiliation(s)
- Huda R M Rashdan
- Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, 33 El Buhouth St, Dokki, Giza, 12622, Egypt.
| | - Sarah Hassan
- Electron Microscopy Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Sara Maher
- Immunology Department, Theodor Bilharz Research Institute, Giza, Egypt
| | - Hend Okasha
- Biochemistry and Molecular Biology Department, Theodor Bilharz Research Institute, Giza, Egypt
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Balachander GM, Ng IC, Pai RR, Mitra K, Tasnim F, Lim YS, Kwok R, Song Y, Yaw LP, Quah CB, Zhao J, Septiana WL, Kota VG, Teng Y, Zheng K, Xu Y, Lim SH, Ng HH, Yu H. LEADS - a comprehensive human liver-on-a-chip for non-alcoholic steatohepatitis (NASH) drug testing. LAB ON A CHIP 2025. [PMID: 40391591 DOI: 10.1039/d5lc00221d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
Metabolic dysfunction associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH), is a progressive form of steatotic liver disease (SLD). It is an emerging healthcare threat due its high prevalence, accelerated and non-linear progression, and final culmination as decompensated liver failure and/or hepatocellular carcinoma (HCC). The pathogenesis of NASH is complex with strong ethnic influences and genetic predispositions, underscoring the need for preclinical models that utilize patient-derived cells to enhance our understanding of the disease. Current models face three major limitations: (i) reliance on primary cells with limited reproducibility, high cost, short culture duration and ethical considerations, (ii) failure to recapitulate all key features of NASH, and (iii) inadequate drug testing data and/or data did not correlate with clinical responses. Therefore, there is a pressing need for robust and relevant preclinical models that faithfully recapitulate human NASH, allow generation of patient-specific models and provide quantitative responses for mechanistic studies and drug testing. We have developed a functional liver tissue-on-a-chip by co-culturing human adult liver stem cell (haLSC)-derived hepatobiliary organoids, induced pluripotent stem cell (iPSC)-derived Kupffer cells (iKCs) and iPSC-derived hepatic stellate cells (iHSCs). We simulated the metabolic microenvironment of hyper nutrition and leaky gut by treating the cells with a concoction of free fatty acids (FFAs), fructose, gut-derived lipopolysaccharides (LPS) and a gut-derived metabolite, phenyl acetic acid (PAA). Through optimization of co-culture media and induction regimens, we were able to stably induce steatosis, hepatocellular ballooning, inflammation, and activation of iHSC and fibrosis-all key hallmarks of NASH. Our LEADS (liver-on-a-chip for NASH drug testing) model also recapitulated the pathological types of steatosis and allowed for quantification of the key features via microscopic evaluation and secretome profiling to score for disease severity. Notably, treatment with saroglitazar, pioglitazone, cenicriviroc (CVC), obeticholic acid (OCA) and resmetirom produced responses similar to those observed in clinical trials. Taken together, our LEADS model is the first model developed using patient-derived hepatic stem cells which recapitulated all key features used for comprehensive drug testing, with results matching to clinical responses.
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Affiliation(s)
- Gowri Manohari Balachander
- School of Biomedical Engineering, Indian Institute of Technology (BHU) Varanasi, Varanasi-221005, India
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Inn Chuan Ng
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Roopesh R Pai
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
- Bioprinting Lab, Department of Dermatology, Dr. D.Y. Patil Medical College, Hospital & Research Centre, Sant Tukaram Nagar, Pimpri, Pune, Maharashtra, India
| | - Kartik Mitra
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Farah Tasnim
- Biomedical Sciences Industry Partnership Office (BMSIPO), A*STAR, 31 Biopolis Way, 138669, Singapore
| | - Yee Siang Lim
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Royston Kwok
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Yoohyun Song
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Lai Ping Yaw
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Clarissa Bernice Quah
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Junzhe Zhao
- Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| | - Wahyunia L Septiana
- Department of Histology, Faculty of Medicine, Gunadarma University, Depok, Indonesia
| | - Vishnu Goutham Kota
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Yao Teng
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Kexiao Zheng
- Nano-Bio-Chem Centre and Organoid Innovation Center, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, 398 Ruoshui Road, Suzhou 215123, China
| | - Yan Xu
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Sei Hien Lim
- AIM Biotech Pte. Ltd., 21 Biopolis Road, #01-24 Nucleos, 138567, Singapore
| | - Huck Hui Ng
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Biological Sciences, National University of Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Hanry Yu
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
- Mechanobiology Institute, National University of Singapore, T-Lab, #05-01, 5A Engineering Drive 1, Singapore 117411, Singapore.
- CAMP, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Level 4 Enterprise Wing, Singapore 138602, Singapore
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Chai TY, George J, Pasupathy D, Cheung NW, Rudland VL. The Maternal and Fetal Consequences of Metabolic Dysfunction-Associated Fatty Liver Disease and Gestational Diabetes Mellitus. Nutrients 2025; 17:1730. [PMID: 40431469 PMCID: PMC12113809 DOI: 10.3390/nu17101730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2025] [Revised: 05/14/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Both metabolic dysfunction-associated fatty liver disease (MAFLD) and gestational diabetes mellitus (GDM) during pregnancy are emerging as an adverse synergistic relationship of growing concern. This narrative review focuses on the maternal and fetal consequences associated with women who have MAFLD and/or GDM during pregnancy, including an exploration of long-term cardiometabolic risks for postpartum maternal and childhood health. We conclude that implementation of a life course approach to management of these high-risk women remains paramount.
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Affiliation(s)
- Thora Y. Chai
- Macarthur Diabetes Service, Campbelltown Hospital, Campbelltown, NSW 2560, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; (J.G.); (D.P.); (N.W.C.); (V.L.R.)
- Reproduction and Perinatal Centre, Faculty of Medicine and Health, Westmead Hospital, The University of Sydney, Westmead, NSW 2145, Australia
| | - Jacob George
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; (J.G.); (D.P.); (N.W.C.); (V.L.R.)
- Storr Liver Centre, Westmead Millennium Institute for Medical Research, Westmead Hospital and The University of Sydney, Westmead, NSW 2145, Australia
- Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, NSW 2145, Australia
| | - Dharmintra Pasupathy
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; (J.G.); (D.P.); (N.W.C.); (V.L.R.)
- Reproduction and Perinatal Centre, Faculty of Medicine and Health, Westmead Hospital, The University of Sydney, Westmead, NSW 2145, Australia
| | - Ngai Wah Cheung
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; (J.G.); (D.P.); (N.W.C.); (V.L.R.)
- Reproduction and Perinatal Centre, Faculty of Medicine and Health, Westmead Hospital, The University of Sydney, Westmead, NSW 2145, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, NSW 2145, Australia
| | - Victoria L. Rudland
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; (J.G.); (D.P.); (N.W.C.); (V.L.R.)
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Fayaz M, Viswanatha GL, Shylaja H, Nandakumar K. Exploring the Hepatoprotective Effects of Naringin: A Systematic Review and Meta-Analysis of Preclinical Evidence. PLANTA MEDICA 2025. [PMID: 40368365 DOI: 10.1055/a-2595-7650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2025]
Abstract
This study aimed to perform a systematic review and meta-analysis on the hepatoprotective effects of naringin based on the pre-clinical evidence.A detailed literature search was performed using online databases such as Google Scholar, PubMed, Scopus, and EMBASE. Based on the predefined inclusion and exclusion criteria, 20 studies were considered for meta-analysis.The outcomes of the meta-analysis revealed that naringin improved liver function by reducing the elevated levels of ALT, AST, GGT, LDH, ALP, and bilirubin. It improved the enzymatic and non-enzymatic antioxidants, such as SOD, catalase, GSH, GST, GR, and GPx (p < 0.05 for all the parameters), while reducing the LPO/MDA levels (p < 0.05). NAR treatment also alleviated the levels of inflammatory mediators (IL-1β, IL-6, and TNF-α, p < 0.001 for all the parameters; NF-κB, p = 0.29) in various animal models of liver injury. In addition, NAR significantly reduced the caspase-3 and Bax/Bcl-2 ratio (p < 0.05) compared to the control group. Furthermore, naringin treatment has normalised the liver and body weights compared to the disease control group.This systematic review and meta-analysis demonstrate that naringin significantly improved the liver function in various animal models of liver injury, via potent antioxidant and anti-inflammatory mechanisms.
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Affiliation(s)
- Muhammed Fayaz
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal - 576104, India
| | | | | | - Krishnadas Nandakumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal - 576104, India
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Algheshairy RM, Alharbi HF, Almujaydil MS, Alhomaid RM, Ali HA. The protective effect of various forms of Nigella sativa against hepatorenal dysfunction: underlying mechanisms comprise antioxidation, anti- inflammation, and anti-apoptosis. Front Nutr 2025; 12:1553215. [PMID: 40432961 PMCID: PMC12106032 DOI: 10.3389/fnut.2025.1553215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 04/21/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction The liver and kidney are vital organs that are interconnected, dealing with detoxifying and excreting xenobiotics. They are constantly exposed to oxidative stress, which can cause hepatorenal dysfunction. This study compares two forms of Nigella sativa (NS), NS oil (NSO), and NS seeds (NSS), for the first time, in their ability to mitigate hepatorenal injury induced by azathioprine (AZA), exploring potential underlying mechanisms. Methods Group (1): negative control; Group (2): positive control received 15 mg/kg AZA orally. Groups (3, 4, and 5) received 100 mg/kg silymarin (standard reference), 500 mg/kg NSO, and 250 mg/kg NSS, respectively, and were subjected to the same dose of AZA. A one-way analysis of variance was conducted, followed by Mann-Whitney post-hoc analysis. Results Administration of AZA induced hepatorenal dysfunction, evidenced by dyslipidemia, elevations in serum liver enzymes, creatinine, urea, pro-inflammatory cytokines, and cytokeratin-18. Antioxidant enzymes in liver and kidney tissues were reduced, with an elevation in caspase-3 and caspase-9. Both forms of NS significantly balanced serum pro- inflammatory cytokines (14.33 ± 2.33, 15.15 ± 1.64 vs. 24.87 ± 1.87) pg/ml, interleukin-4 (16.72 ± 1.14, 15.95 ± 1.03 vs. 10.64 ± 1.04) pg/ml, and interleukin-10 (19.89 ± 0.69, 18.38 ± 0.38 vs. 15.52 ± 1.02) pg/ml, and downregulated cytokeratin-18 (210.43 ± 21.56, 195.86 ± 19.42 vs. 296.54 ± 13.94) pg/ml for NSO and NSS vs. the positive group, respectively. NSS enhanced liver antioxidant activity (P < 0.05), normalized liver enzymes (P < 0.05, P < 0.01) for alanine aminotransferase and aspartate aminotransferase, respectively, and significantly lessened dyslipidemia (P < 0.05). Liver caspase-3 and caspase-9 improved significantly with NSS, while kidney caspase-3 and caspase-9 improved with NSO. NSO increased kidney glutathione peroxidase and catalase (P < 0.01) and corrected creatinine and urea (P < 0.05). Histopathological observations confirmed the present data. Discussion Conclusively, NSO and NSS mitigated hepatorenal dysfunction responses to AZA through antioxidant, anti-inflammatory, and anti-apoptosis properties that underlie their protective performance. Interestingly, NSO surpassed NSS in restoring renal oxidative damage, while NSS provided better hepatic protection than NSO, suggesting NSO for patients with kidney dysfunction and NSS for those with liver problems.
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Affiliation(s)
- Reham M. Algheshairy
- Department of Food Science and Human Nutrition, College of Agriculture and Food, Qassim University, Buraydah, Saudi Arabia
| | - Hend F. Alharbi
- Department of Food Science and Human Nutrition, College of Agriculture and Food, Qassim University, Buraydah, Saudi Arabia
| | - Mona S. Almujaydil
- Department of Food Science and Human Nutrition, College of Agriculture and Food, Qassim University, Buraydah, Saudi Arabia
| | - Raghad M. Alhomaid
- Department of Food Science and Human Nutrition, College of Agriculture and Food, Qassim University, Buraydah, Saudi Arabia
| | - Hoda A. Ali
- Department of Nutrition and Clinical Nutrition, College of Veterinary Medicine, Cairo University, Cairo, Egypt
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Sah AK, Afzal M, Elshaikh RH, Abbas AM, Shalabi MG, Prabhakar PK, Babker AMA, Khalimova FT, Sabrievna VA, Choudhary RK. Innovative Strategies in the Diagnosis and Treatment of Liver Cirrhosis and Associated Syndromes. Life (Basel) 2025; 15:779. [PMID: 40430206 PMCID: PMC12112768 DOI: 10.3390/life15050779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Revised: 04/27/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Liver cirrhosis continues to be a major global health issue, contributing to high morbidity and mortality due to its progressive nature and associated complications. This review explores recent advancements in the diagnosis and treatment of liver cirrhosis and its related syndromes. Non-invasive diagnostic tools, such as elastography and serum biomarkers, have significantly improved early detection, reducing the need for liver biopsies. Advanced imaging techniques, including MRI and CT, further enhance diagnostic accuracy. In parallel, molecular and genomic research is providing new insights into the pathogenesis of the disease, paving the way for precision medicine. On the treatment front, pharmacological innovations, such as antifibrotic agents and targeted therapies, show promise in slowing disease progression. Endoscopic interventions like variceal banding are improving the management of complications, while advancements in liver transplantation and artificial liver support systems offer life-saving alternatives. Regenerative medicine, particularly stem cell therapy and tissue engineering, is emerging as a promising strategy for liver repair. Managing cirrhosis-related syndromes, including portal hypertension, ascites, hepatic encephalopathy, and hepatorenal syndrome, now involves evolving therapeutic approaches such as transjugular intrahepatic portosystemic shunt (TIPS) and novel pharmacotherapies. Prognostic scoring systems like the MELD and Child-Pugh are being refined with new biomarkers for better risk stratification. The future of cirrhosis care will likely involve the integration of artificial intelligence and machine learning for early diagnosis and personalized treatments, alongside emerging therapies currently under investigation. Despite these advancements, challenges such as costs, accessibility, and healthcare disparities remain barriers to widespread adoption. This review highlights the importance of incorporating innovative diagnostic and therapeutic strategies into clinical practice to improve the outcomes for patients with liver cirrhosis and its complications.
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Affiliation(s)
- Ashok Kumar Sah
- Department of Medical Laboratory Sciences, College of Applied and Health Sciences, A’ Sharqiyah University, Ibra 400, Oman;
| | - Mohd Afzal
- Department of Medical Laboratory Technology, Arogyam Institute of Paramedical & Allied Sciences (Affiliated to H.N.B. Uttarakhand Medical Education University), Roorkee 247661, India;
| | - Rabab H. Elshaikh
- Department of Medical Laboratory Sciences, College of Applied and Health Sciences, A’ Sharqiyah University, Ibra 400, Oman;
| | - Anass M. Abbas
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia; (A.M.A.); (M.G.S.)
| | - Manar G. Shalabi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia; (A.M.A.); (M.G.S.)
| | - Pranav Kumar Prabhakar
- Department of Biotechnology, School of Engineering and Technology, Nagaland University, Meriema, Kohima 797004, India;
| | - Asaad M. A. Babker
- Department of Medical Laboratory Sciences, College of Health Sciences, Gulf Medical University, Ajman 4184, United Arab Emirates;
| | | | - Velilyaeva Aliya Sabrievna
- Department of Psychiatry, Medical Psychology, and Narcology, Samarkand State Medical University, Samarkand 140158, Uzbekistan
| | - Ranjay Kumar Choudhary
- Department of Medical Laboratory Technology, University Institute of Allied Health Sciences, Chandigarh University, Chandigarh 140413, India
- School of Paramedics and Allied Health Sciences, Centurion University of Technology and Management, Sitapur 761211, India
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Ololade ZS, Anuoluwa IA, Onifade OF, Adeagbo AI, Oyebanji OT, Asaju AO, Eze JC. Evaluation of Annona muricata for hepatoprotection, hematological assessment and inhibitor of TGFβR1 in liver diseases. Arch Physiol Biochem 2025:1-18. [PMID: 40364510 DOI: 10.1080/13813455.2025.2499840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 04/05/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND This study was conducted to assess the hepatoprotective potential of Annona muricata flower (AMF) using albino rats' model. MATERIALS AND METHODS Liver function assays such as alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBILI), antioxidants, haematology (HGB), histology, inhibition of transforming growth factor beta receptor I (TGFβR1) and antibacterial assays were investigated. RESULTS AND DISCUSSION Induction with acetaminophen gave rise to a significant increase (p < 0.05) in serum of liver enzymes of ALT, AST, ALP and TBILI in the acetaminophen (APAP) only group, which indicates hepatocellular injury, whereas AMF attenuated liver enzymes level. The histological assessment confirmed that AMF possesses blood-enhancing ability. AMF significantly showed inhibition of TGFβR1. AMF was active against all the tested bacteria with high zones of inhibition. CONCLUSION This study provides information on the uses of AMF as a natural product for hepatoprotection and other therapeutic purposes.
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Affiliation(s)
- Zacchaeus S Ololade
- Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmacy, University of Medical Sciences, Ondo, Nigeria
- Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria
| | | | - Olayinka F Onifade
- Department of Chemical and Food Sciences, Biochemistry Unit, Bells University of Technology, Ota, Nigeria
| | - Adewumi I Adeagbo
- Department of Physical Sciences Education, Emmanuel Alayande University, Oyo, Nigeria
| | - Olawumi T Oyebanji
- Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria
| | - Ademola O Asaju
- Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria
| | - John C Eze
- Department of Chemistry, Medicinal and Organic Chemistry Unit, University of Medical Sciences, Ondo, Nigeria
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Xu Z, Xu B. Nonlinear association between AST/ALT ratio and 28-day all-cause mortality following ICU admission in critically ill cirrhotic patients: a retrospective cohort study. BMC Gastroenterol 2025; 25:367. [PMID: 40360992 PMCID: PMC12070544 DOI: 10.1186/s12876-025-03966-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND The AST/ALT ratio is a biochemical marker associated with poor clinical outcomes in various patients, but its role in severe cirrhosis is unclear. This study investigated the relationship between the AST/ALT ratio and mortality in the intensive care unit (ICU) patients with cirrhosis. METHODS This retrospective cohort study analyzed 2,090 liver cirrhosis patients from the MIMIC-IV database, focusing on their first ICU admission between 2008 and 2019. The AST/ALT ratio, measured within 24 h of admission, was the exposure variable, and the main outcome was 28-day mortality. A multivariable logistic regression model evaluated the link between the AST/ALT ratio and mortality. Nonlinear relationships were explored using smooth curve fitting and saturation effect analyses. Stratified analyses and interaction tests were also performed based on demographic and clinical characteristics. RESULTS The study involved 2,090 critically ill liver cirrhosis patients, averaging 59.1 years old, with 65% male and a 28-day post-ICU admission mortality rate of 29%. The AST/ALT ratio was linked to mortality risk (adjusted odds ratio (OR) 1.1, 95% confidence interval (CI) 1.0-1.2; p = 0.015), showing a nonlinear pattern with a critical point at 3.6. Below this, each unit increase raised mortality risk by 40% (adjusted OR 1.4, 95% CI 1.2-1.6, p < 0.001), but the effect plateaued beyond this level (adjusted OR 1.0, 95% CI 0.8-1.1, p = 0.600). Subgroup analyses confirmed the consistent association, with interaction P values over 0.05. CONCLUSIONS The AST/ALT ratio is an independent predictor of 28-day mortality in critically ill cirrhotic patients, with a nonlinear relationship (risk increases up to a ratio of ~ 3.6, then plateaus). This marker could enhance ICU risk stratification and inform clinical decision-making.
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Affiliation(s)
- Zhigang Xu
- Department of Gastroenterology, Beijing Luhe Hospital Affiliated to Capital Medical University, Tongzhou District, No. 82 Xinhuanan Road, Beijing, 101149, China
| | - Baohong Xu
- Department of Gastroenterology, Beijing Luhe Hospital Affiliated to Capital Medical University, Tongzhou District, No. 82 Xinhuanan Road, Beijing, 101149, China.
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Akambase JA, Ali Y, Goble SR. The Impact of Housing Insecurity on Hospitalized Patients With Diagnosis of Cirrhosis: A Comparative Analysis Using Data from the National Inpatient Sample. J Clin Gastroenterol 2025:00004836-990000000-00447. [PMID: 40374184 DOI: 10.1097/mcg.0000000000002193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Accepted: 03/25/2025] [Indexed: 05/17/2025]
Abstract
BACKGROUND The impact of homelessness on clinical outcomes and health care utilization among hospitalized cirrhosis patients has not been well-characterized. METHODS We conducted a cross-sectional study using the National Inpatient Sample (2016 to 2021) to analyze hospitalizations of adults with cirrhosis, comparing outcomes between those with and without homelessness. Demographic, clinical, and hospital-level characteristics were assessed, along with outcomes such as mortality and AMA discharges. Health care utilization metrics, including length of stay (LOS) and cost, were also evaluated, with multivariable regression used to adjust for confounders. RESULTS Among 4,579,858 hospitalizations for cirrhosis, 109,640 (2.4%) involved homeless patients, who were younger (mean 53.5 vs. 60.6 y, P<0.001) and predominantly male (80.4% vs. 58.9%, P<0.001). Homeless patients had higher rates of alcohol use (73.5% vs. 30.9%, P<0.001), opioid use disorder (11.8% vs. 3.6%, P<0.001), and psychiatric comorbidities (62% vs. 37.4%, P<0.001). Hispanic and Native American patients were over-represented, while white patients were under-represented. Mortality was lower in homeless patients (aOR=0.49, 95% CI: 0.45-0.54, P<0.001). However, AMA discharges were significantly higher (9.6% vs. 2.7%, P<0.001). Homeless patients had longer hospital stays (mean 7.3 vs. 6.2 d, P<0.001) but lower per-day hospitalization costs ($2278 vs. $2859, P<0.001). CONCLUSION Despite lower mortality rates and cost per hospitalization day, high AMA discharge rates and prolonged hospital stays underscore the challenges to safe discharge among patients with cirrhosis experiencing homelessness.
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Affiliation(s)
| | - Yasmin Ali
- Department of Medicine, Hennepin Healthcare
| | - Spencer R Goble
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Minnesota, Minneapolis, MN
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Gao Y, Chen J, Du W. Identification of novel potential biomarkers using bulk RNA and single cells to build a neural network model for diagnosis of liver cancer. Discov Oncol 2025; 16:728. [PMID: 40353917 PMCID: PMC12069198 DOI: 10.1007/s12672-025-02420-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Accepted: 04/17/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND As a common cancer, liver cancer imposes an unacceptable burden on patients, but its underlying molecular mechanisms are still not fully understood. Therefore, there is an urgent need to potential biomarkers and diagnostic models for liver cancer. METHODS In this study, transcriptome and single-cell datasets related to liver cancer were downloaded from the UCSC Xena database and the Mendeley database, and differential analysis and weighted gene co-expression network analysis were used to find differentially expressed genes related to liver cancer. We used multiple machine algorithms to find hub genes related to liver cancer, and constructed new artificial neural network models based on their transcriptome expression patterns to assist in the diagnosis of liver cancer. Subsequently, we conducted survival analysis and immune infiltration analysis to explore the correlation between hub genes and immune cells, and used single-cell data to verify hub genes related to liver cancer. RESULTS This study identified MARCO, KCNN2, NTS, TERT and SFRP4 as central genes associated with liver cancer, and constructed a new artificial neural network model for molecular diagnosis of liver cancer. The diagnostic performance of the training cohort and the validation cohort was good, with the areas under the ROC curves of 1.000 and 0.986, respectively. Immune infiltration analysis determined that these central genes were closely associated with different types of immune cells. The results of immunohistochemistry and the results at the single cell level were consistent with those at the transcriptome level, and also showed obvious differences between different cell types in liver cancer and healthy states. CONCLUSION This study identified MARCO, KCNN2, NTS, TERT, and SFRP4 from multiple dimensions and highlighted their key roles in the diagnosis and treatment of liver cancer from multiple dimensions, providing promising biomarkers for the diagnosis of liver cancer.
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Affiliation(s)
- Yingzheng Gao
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Jiahao Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310006, China
| | - Weidong Du
- The First Affiliated Hospital of Zhejiang, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Chinese Medical University, Hangzhou, 310006, China.
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Xue Y, Tian T, Ottallah M, Mannan M, Barkin J, Jin-Smith B, Pi L. Alcohol-Associated Hepatocarcinogenesis: Wnt/β-Catenin in Action. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00156-7. [PMID: 40350059 DOI: 10.1016/j.ajpath.2025.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/06/2025] [Accepted: 04/14/2025] [Indexed: 05/14/2025]
Abstract
Long-term alcohol consumption is a leading global health concern, primarily due to its deleterious effects on liver function and its well-established association with hepatocellular carcinoma. Alcohol-related liver disease (ALD) encompasses a continuum-from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt hepatocellular carcinoma. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunologic, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix remodeling, and alters hepatocyte cell fate, thereby creating a microenvironment that is highly conducive to carcinogenesis. This article provides a systematic review of the significant function of Wnt/β-catenin signaling in ALD, emphasizing its regulatory impact on liver fat accumulation, its inflammatory role in steatohepatitis, its involvement in fibrogenesis, and its tumor-promoting effects in alcohol-related hepatocellular carcinoma. In addition, emerging therapeutic strategies that offer potential for early identification and tailored therapy of ALD are explored-including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches.
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Affiliation(s)
- Yuhua Xue
- Department of Pathology, Tulane University, New Orleans, Louisiana
| | - Tian Tian
- Department of Pathology, Tulane University, New Orleans, Louisiana
| | - Melak Ottallah
- Department of Pathology, Tulane University, New Orleans, Louisiana
| | - Mahfuza Mannan
- Department of Pathology, Tulane University, New Orleans, Louisiana
| | - Joshua Barkin
- Department of Pathology, Tulane University, New Orleans, Louisiana
| | - Brady Jin-Smith
- Department of Pathology, Tulane University, New Orleans, Louisiana
| | - Liya Pi
- Department of Pathology, Tulane University, New Orleans, Louisiana.
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Tseng YT, Wang CH, Wang JD, Chen KT, Li CY. Nonlinear associations of serum vitamin D levels with advanced liver disease and mortality: a US Cohort Study. Therap Adv Gastroenterol 2025; 18:17562848251338669. [PMID: 40351383 PMCID: PMC12062647 DOI: 10.1177/17562848251338669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 04/12/2025] [Indexed: 05/14/2025] Open
Abstract
Background Vitamin D deficiency is prevalent and linked to chronic diseases; its association with advanced liver disease progression requires clarification. Objectives To investigate the association between vitamin D levels and risks of liver cirrhosis, hepatocellular carcinoma (HCC), and mortality, and assess risk changes after achieving sufficiency post-supplementation. Design This was a retrospective cohort study. Methods Utilized TriNetX US data (3,905,594 patients, 2000-2024). Adults with vitamin D deficiency (20.00-30.00 ng/mL) were compared with those with sufficient levels (30.01-80.00 ng/mL). Follow-up was initiated from the first vitamin D test or start of supplementation to minimize immortal time bias. Propensity score matching (1:1) balanced >20 baseline confounders. Results After matching, 1,204,760 patients with vitamin D deficiency and 1,204,760 with sufficient vitamin D levels were included. Vitamin D deficiency was associated with an increased risk of liver cirrhosis (hazard ratio (HR), 1.30; 95% confidence interval (CI), 1.25-1.36), HCC (HR, 1.22; 95% CI, 1.08-1.37), and all-cause mortality (HR, 1.14; 95% CI, 1.13-1.16). Achieving sufficient vitamin D levels reduced the risk of all-cause mortality (HR, 0.93; 95% CI, 0.88-0.99) and aligned HCC outcomes (HR, 1.16; 95% CI, 0.68-2.00). However, it did not significantly reduce the risk of liver cirrhosis (HR, 2.05; 95% CI, 1.69-2.50). Dose-response analysis showed a U-shaped relationship for liver cirrhosis and HCC, with the lowest risks at 40-60 ng/mL. Conclusion Serum vitamin D levels showed a nonlinear association with liver cirrhosis and HCC risk; deficiency independently increased the risks for cirrhosis, HCC, and mortality. Supplementation achieving sufficiency reduced mortality and normalized HCC risk but not cirrhosis risk, potentially reflecting limitations in reversing established disease. The lowest liver disease risk was associated with vitamin D levels of 40-60 ng/mL in this cohort, although causality and the clinical benefit of targeting this specific range require confirmation.
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Affiliation(s)
- Yuan-Tsung Tseng
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Department of Medical Research, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan City, Taiwan
| | - Chun-Hsiang Wang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan City, Taiwan
| | - Jung-Der Wang
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Kow-Tong Chen
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
- Department of Occupational Medicine, Tainan Municipal Hospital (managed by Show Chwan Medical Care Corporation), Tainan City, Taiwan
| | - Chung-Yi Li
- Department of Public Health, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan City 701, Taiwan
- Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan
- Department of Healthcare Administration, College of Medical and Health Science, Taichung, Taiwan
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Li Y, Cao Z, Lu Y, Lei C, Lyu W. Knowledge landscape of macrophage research in liver fibrosis: a bibliometric review of the literature from WoSCC. Front Pharmacol 2025; 16:1571879. [PMID: 40406489 PMCID: PMC12094998 DOI: 10.3389/fphar.2025.1571879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 04/16/2025] [Indexed: 05/26/2025] Open
Abstract
Recent insights into the immune response in fibrosis have provided valuable perspectives for the treatment of liver fibrosis. Macrophages, as the most abundant immune cells in the liver, are key drivers of liver fibrosis. They are extensively involved in tissue damage, chronic inflammation, and the progression and regression of liver fibrosis. This study aims to conduct a bibliometric analysis and literature review on the mechanisms by which macrophages contribute to liver fibrosis. Specifically, we analyzed a bibliometric dataset comprising 1,312 papers from 59 countries, 1,872 institutions, and 9,784 authors. Keyword co-occurrence analysis identified key research hotspots, including the role of macrophage subtypes in obesity-related metabolic disorders, the crosstalk between macrophages and hepatic stellate cells through mechanoimmunology, emerging strategies for immune modulation targeting macrophages to promote fibrosis regression and liver regeneration, and new discoveries regarding macrophage crosstalk with other immune cells. In conclusion, this study provides a visual analysis of the current research landscape, hotspots, and trends in the field of macrophages and liver fibrosis, and discusses future directions for further exploration in this area.
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Affiliation(s)
- Yanbo Li
- Department of Infectious Diseases, Guang’anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing, China
| | - Zhengmin Cao
- Department of Infectious Diseases, Guang’anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing, China
| | - Yanping Lu
- Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Chao Lei
- Department of Infectious Diseases, Guang’anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing, China
| | - Wenliang Lyu
- Department of Infectious Diseases, Guang’anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing, China
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Huang H, Ru SJ, Chen JM, Liu W, Fang SH, Liu Q, Meng Q, Liu P, Zhou H. Quantitative Proteomic Study Reveals Amygdalin Alleviates Liver Fibrosis Through Inhibiting mTOR/PDCD4/JNK Pathway in Hepatic Stellate Cells. Drug Des Devel Ther 2025; 19:3735-3749. [PMID: 40356680 PMCID: PMC12067723 DOI: 10.2147/dddt.s500439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Accepted: 04/05/2025] [Indexed: 05/15/2025] Open
Abstract
Purpose Hepatic fibrosis is a major cause of morbidity and mortality for which there is currently limited therapy. Amygdalin, a cyanogenic glucoside derived from Semen Persicae, exerts significant anti-fibrotic effects in the liver. However, the molecular mechanism by which amygdalin inhibits the progression of liver fibrosis remains unclear. This study aimed to elucidate the potential mechanism of action of amygdalin against liver fibrosis. Methods Quantitative proteomic profiling of the mouse liver tissues from control, carbon tetrachloride (CCl4)-induced fibrosis, and amygdalin-treated groups was performed to explore the key effector proteins of amygdalin. Histology and immunohistochemistry as well as serum biochemical analysis were performed to evaluate amygdalin efficacy in mice. The key gene programmed cell death protein 4 (PDCD4) was overexpressed or knocked down in human hepatic stellate cells (HSCs). The mRNA and protein levels of related molecules were detected by RT-qPCR and Western blotting, respectively. Results Amygdalin could effectively ameliorated CCl4-induced liver fibrosis in mice. Bioinformatics analysis revealed that PDCD4 was downregulated in CCl4-induced liver fibrosis, but amygdalin treatment reversed these changes. An in vitro study showed that PDCD4 inhibited the activation of human hepatic stellate cell line LX-2 cells by regulating the JNK/c-Jun pathway and amygdalin inhibited the activation of LX-2 cells in a PDCD4-dependent manner. We further found that amygdalin inhibited the phosphorylation of PDCD4 at Ser67 by inhibiting the mTOR/S6K1 pathway to enhance PDCD4 expression. Conclusion Our data demonstrated a potential pharmaceutical mechanism by which amygdalin alleviates liver fibrosis by inhibiting the mTOR/PDCD4/JNK pathway in HSCs, suggesting that PDCD4 is a potential target for the treatment of liver fibrosis.
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Affiliation(s)
- Hui Huang
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, People’s Republic of China
- Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Su-Jie Ru
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
| | - Jia-Mei Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, People’s Republic of China
| | - Wei Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, People’s Republic of China
| | - Shan-Hua Fang
- Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Qian Liu
- Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Qian Meng
- Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China
| | - Ping Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, People’s Republic of China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Hu Zhou
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, People’s Republic of China
- Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China
- University of Chinese Academy of Sciences, Beijing, People’s Republic of China
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Yang X, Ma J, Li H. Trajectories of depressive symptoms and risk of chronic liver disease: evidence from CHARLS. BMC Gastroenterol 2025; 25:338. [PMID: 40335900 PMCID: PMC12057118 DOI: 10.1186/s12876-025-03943-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 04/25/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND It is unclear whether there is a association between the long-term depressive symptoms and chronic liver disease(CLD). The aim of present study was to investigate the relationship between the trajectories of depressive symptoms and CLD in middle-aged and older Chinese adults. METHODS The study included data from 7351 Chinese individuals, which from the China Health and Retirement Longitudinal Study (CHARLS). Latent Class Growth Model (LCGM) and Growth Mixture Model (GMM) identified five categories of depressive symptom trajectories from 2011 to 2015. Multiple logistic regression models were used to analyze the relationship between depressive symptom trajectories and CLD in 2015-2020. RESULTS We identified five distinct trajectories of depressive symptoms characterized by persistent low CES-D scores throughout follow-up (low-stable; 4621 cases [62.86%]); high starting CES-D scores but then declining (high-decreasing; 824 cases [11.21%]); persistent high CES-D scores during follow-up (high-stable; 508 cases [6.91%]); starting moderate CES-D scores but then increasing (moderate-increasing; 844 cases [11.48%]); and low starting CES-D scores that increased and then remitted through follow-up (remitting; 554 cases [7.54%]). A total of 420 (5.71%) participants developed chronic liver disease during follow-up. The ORs (95% CI) for the risk of developing chronic liver disease in participants on the moderate-increasing trajectory, high-decreasing trajectory, and high-stable trajectory were 1.44 (1.05-1.93), 1.59 (1.17-2.12), and 2.25 (1.62-3.08), respectively, compared with participants on the low-stable trajectory. CONCLUSION In Chinese middle-aged and older adults, individuals with moderate-increasing, high-decreasing, and high-stable trajectories of depressive symptoms over time had an increased risk of developing CLD.
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Affiliation(s)
- Xikun Yang
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan, China
| | - Jiangping Ma
- Department of Neurology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Tongji University School of Medicine, Shanghai, China
| | - Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan, China.
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, Sichuan, China.
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Sun CY, Wang YN, Zhan HF, Sun Y, Guan YP, Lin Y, Cai LY, Zeng X. Geriatric Nutritional Risk Index as a Predictor of Overall Survival in Cirrhosis: A Retrospective Cohort Study. Curr Med Sci 2025:10.1007/s11596-025-00056-w. [PMID: 40332738 DOI: 10.1007/s11596-025-00056-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 04/12/2025] [Accepted: 04/16/2025] [Indexed: 05/08/2025]
Abstract
OBJECTIVE The geriatric nutritional risk index (GNRI) is widely used for nutritional assessment. Poor nutritional status is associated with complications and poor survival in cirrhotic patients. We aimed to investigate the value of the GNRI in predicting outcomes in cirrhotic patients. METHODS This retrospective study included 420 cirrhotic patients from three centers between 2013 and 2017. Patients were divided into the high GNRI group (≥ 92) and low GNRI group (< 92). Overall survival (OS) in the two groups was evaluated via the Kaplan‒Meier method. Cox proportional hazards model was used to estimate the value of the GNRI in predicting outcomes. Restricted cubic spline model was used to intuitively display the dose‒response associations between the GNRI and OS. A nomogram was constructed to predict OS. RESULTS During the 2-year follow-up period, 58 (13.81%) patients died, and 262 (62.38%) patients experienced episodes of complications. Compared with patients in the low GNRI group, those in the high GNRI group had lower mortality rates (18.73% vs. 5.23%, P < 0.001). The GNRI was an independent predictor of OS (hazard ratio [HR] = 0.958, 95% confidence interval [CI] 0.929-0.988, P = 0.007). The GNRI was associated with the cumulative incidence of ascites (HR = 0. 954, 95% CI 0.940-0.969, P < 0.001), spontaneous bacterial peritonitis (HR = 0.928, 95% CI 0.891-0.966, P < 0.001), hepatic encephalopathy (HE; HR = 0.944, 95% CI 0.920-0.968, P < 0.001), and hepatorenal syndrome (HRS) (HR = 0.916, 95% CI 0.861-0.974, P = 0.005). Furthermore, 6 independent factors were included to construct the nomogram for OS prediction, including GNRI, age, total bilirubin, serum sodium, history of HE and HRS. The C statistics of our model were 0.83 (95% CI 0.75-0.90) and 0.80 (95% CI 0.73-0.86) at 1 and 2 years, respectively. Patients whose GNRI score decreased within 3 and 6 months had poorer outcomes (P < 0.001). CONCLUSIONS The lower GNRI score was associated with the higher cumulative incidence of complications and poorer OS of cirrhotic patients. The GNRI could be a helpful tool for assessing nutritional status and prognosis of these patients.
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Affiliation(s)
- Chun-Yan Sun
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Yu-Ning Wang
- Department of Clinical Medicine, Anhui Medical University, Hefei, 230032, China
| | - Hong-Fei Zhan
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Yan Sun
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Ya-Ping Guan
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Yong Lin
- Department of Gastroenterology, Changzheng Hospital, Navy Military Medical University, Shanghai, 200003, China
| | - Ling-Yan Cai
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
| | - Xin Zeng
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
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Savaş S. Explainable Artificial Intelligence for Diagnosis and Staging of Liver Cirrhosis Using Stacked Ensemble and Multi-Task Learning. Diagnostics (Basel) 2025; 15:1177. [PMID: 40361994 PMCID: PMC12071678 DOI: 10.3390/diagnostics15091177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 04/26/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
Background/Objectives: Liver cirrhosis is a critical chronic condition with increasing global mortality and morbidity rates, emphasizing the necessity for early and accurate diagnosis. This study proposes a comprehensive deep-learning framework for the automatic diagnosis and staging of liver cirrhosis using T2-weighted MRI images. Methods: The methodology integrates stacked ensemble learning, multi-task learning (MTL), and transfer learning within an explainable artificial intelligence (XAI) context to improve diagnostic accuracy, reliability, and transparency. A hybrid model combining multiple pre-trained convolutional neural networks (VGG16, MobileNet, and DenseNet121) with XGBoost as a meta-classifier demonstrated robust performance in binary classification between healthy and cirrhotic cases. Results: The model achieved a mean accuracy of 96.92%, precision of 95.12%, recall of 98.93%, and F1-score of 96.98% across 10-fold cross-validation. For staging (mild, moderate, and severe), the MTL framework reached a main task accuracy of 96.71% and an average AUC of 99.81%, with a powerful performance in identifying severe cases. Grad-CAM visualizations reveal class-specific activation regions, enhancing the transparency and trust in the model's decision-making. The proposed system was validated using the CirrMRI600+ dataset with a 10-fold cross-validation strategy, achieving high accuracy (AUC: 99.7%) and consistent results across folds. Conclusions: This research not only advances State-of-the-Art diagnostic methods but also addresses the black-box nature of deep learning in clinical applications. The framework offers potential as a decision-support system for radiologists, contributing to early detection, effective staging, personalized treatment planning, and better-informed treatment planning for liver cirrhosis.
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Affiliation(s)
- Serkan Savaş
- Department of Computer Engineering, Faculty of Engineering and Natural Sciences, Kırıkkale University, Kırıkkale 71450, Türkiye
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Kermani F, Mahmoodi M, Nasiri MR, Orooji A. Quality review and content analysis of liver complications mobile apps in Iran: A statistical and machine learning approach. Int J Med Inform 2025; 197:105842. [PMID: 39970492 DOI: 10.1016/j.ijmedinf.2025.105842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 02/13/2025] [Accepted: 02/17/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Liver disease accounts for 4 % of global mortality. The advent of mobile technology has introduced a novel domain in liver disease management. Identifying effective mobile apps with pertinent information on liver diseases is essential. This study seeks to evaluate liver disease-related mobile applications using the Mobile Application Rating Scale (MARS) quality assessment tool. METHOD This research employs a cross-sectional descriptive and analytical methodology focusing on liver disease-related mobile applications. We evaluated all Persian and English mobile applications available on the Google Play, Cafe Bazaar, and Myket Stores dedicated to liver diseases until 2023. After eliminating duplicates, evaluators extracted technical specifications and features of apps. The MARS was employed to assess the quality of the mobile applications. Both statistical and machine learning methods were employed for analysis. RESULTS A total of 2,044 mobile applications were identified, with 49 selected for final analysis. The apps focused on liver-related issues included general liver disease (n = 20, 40.82 %), hepatitis (n = 9, 18.37 %), and fatty liver disease (n = 8, 16.33 %). In terms of functionality, the majority of apps (n = 20, 40.82 %) served as calculators, with 15 specifically for calculation. Among these, three integrated educational elements, and two also supported diet and fitness alongside calculator functions. Additionally, 20 apps aimed to provide educational and informative content. The average quality score was 3.17 (SD = 0.20), with scores ranging from 2.33 to 4.45. Generally, the mean score of Engagement, Functionality, Aesthetics and Information were 4.20 (SD = 0.67), 4.00 (SD = 0.67), 4.00 (SD = 0.92), and 4.00 (SD = 0.67), respectively. The highest Subjective quality score was 4.75. CONCLUSIONS Liver disease-related mobile applications serve users in educational, diet and lifestyle, calculation, risk assessment, and management domains, focusing mainly on general liver diseases and hepatitis. However, the results revealed that the apps lack sufficient and reliable information.
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Affiliation(s)
- Farzaneh Kermani
- Social Determinants of Health Research Center, Semnan University of Medical Sciences, Semnan, Iran; Department of Health Information Technology, Sorkheh School of Allied Medical Sciences, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahdi Mahmoodi
- Student Research Committee, Semnan University of Medical, Semnan, Iran
| | | | - Azam Orooji
- Department of Medical Biotechnology, School of Medicine, North Khorasan University of Medical Science (NKUMS), Bojnourd, Iran.
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Liu Z, Jiang X, You H, Tang Z, Ma Y, Che N, Liu W, Ma C. Extracellular vesicles derived from bone marrow mesenchymal stem cells ameliorate liver fibrosis via micro-7045-5p. Mol Cell Biochem 2025; 480:2903-2921. [PMID: 39516341 DOI: 10.1007/s11010-024-05152-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Liver fibrosis is a crucial pathological factor in the persistence and progression of chronic liver disease. Increasing evidence has demonstrated the significant potential of extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) in the clinical treatment of liver fibrosis. This study aimed to mechanistically investigate the impact of BMSC-derived EVs (BMSC-EVs) containing miR-7045-5p on the autophagy of activated hepatic stellate cells (HSCs) during liver fibrosis. METHOD BMSCs were isolated from the bilateral femurs and tibiae of mice. Their identity was confirmed via immunofluorescence staining for the BMSC marker CD44. EVs were harvested from BMSC culture medium at passages 3-5 and then DiR-labeled. Labeled BMSC-EVs were co-cultured with the HSC-T6 cell line to determine their uptake and sub-cellular localization in HSCs. Various methods, such as western blotting, qRT-PCR, and ELISA, were employed to assess the effects of BMSC-EVs on the fibrotic activation (marked by COL1-A1 and α-SMA expression) and autophagy (p62, Atg16L1, Beclin-1, and LC3 expression) of HSC-T6 cells. Additionally, the BMSC-EV-induced changes in autophagy-related signaling pathways (PI3K, AKT, and mTOR pathways) in these cells were evaluated. Finally, the gene-chip detection technology was utilized to predict the involvement of BMSC-EV-derived miRNAs (BMSC-EV-miRs) in the observed effects, with a focus on miR-7045-5p, and our findings were validated in HSCs transfected with a miR-7045-5p mimic. RESULT The gene-chip detection results indicated that miR-7045-5p was enriched in BMSC-EVs compared with BMSCs and targeted Akt. In the CCl4-induced mouse model of liver fibrosis, BMSC-EV-miR-7045-5p ameliorated the fibrosis and enhanced liver function by suppressing the PI3K/Akt/mTOR signaling pathway. Additionally, miR-7045-5p inhibited TGF-β1-induced fibrotic activation of HSC-T6 cells. CONCLUSION BMSC-EVs promote autophagy in HSC-T6 cells and alleviate liver fibrosis by inhibiting the PI3K/Akt/mTOR signaling pathway at least in part by delivering anti-fibrotic miRNAs, such as miR-7045-5p.
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Affiliation(s)
- Zhejun Liu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Xiaodan Jiang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Hongjie You
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zuoqing Tang
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yun Ma
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Niancong Che
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Wenlan Liu
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
| | - Chongyang Ma
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
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Nie YM, Zhou WQ, Niu T, Mao MF, Zhan YX, Li Y, Wang KP, Li MX, Ding K. Peptidoglycan isolated from the fruit of Lycium barbarum alleviates liver fibrosis in mice by regulating the TGF-β/Smad7 signaling and gut microbiota. Acta Pharmacol Sin 2025; 46:1329-1344. [PMID: 39833303 PMCID: PMC12032012 DOI: 10.1038/s41401-024-01454-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 12/09/2024] [Indexed: 01/22/2025]
Abstract
The hepatoprotective effect of the fruit of Lycium barbarum has been documented in China over millennia. Lycium barbarum polysaccharides (LBPs) were the first macromolecules reported to mitigate liver fibrosis in carbon tetrachloride (CCl4)-treated mice. Herein, a neutral peptidoglycan, named as LBPW, was extracted from the fruit of Lycium barbarum. In this study, we investigated the hepatoprotective mechanisms of LBPW. CCl4-induced liver fibrosis mice were administered LBPW (50, 100, 200 mg ·kg-1 ·d-1, i.p.) or (100, 200, 300 mg· kg-1 ·d-1, i.g.) for 6 weeks. We showed that either i.p. or i.g. administration of LBPW dose-dependently attenuated liver damage and fibrosis in CCl4-treated mice. Pharmacokinetic analysis showed that cyanine 5.5 amine (Cy5.5)-labeled LBPW (Cy5.5-LBPW) could be detected in the liver through i.p. and i.g. administration with i.g.-administered Cy5.5-LBPW mainly accumulating in the intestine. In TGF-β1-stimulated LX-2 cells as well as in the liver of CCl4-treated mice, we demonstrated that LBPW significantly upregulated Smad7, a negative regulator of TGF-β/Smad signaling, to retard the activation of hepatic stellate cells (HSCs) and prevent liver fibrosis. On the other hand, LBPW significantly boosted the abundance of Akkermansia muciniphila (A. muciniphila) and fortified gut barrier function. We demonstrated that A. muciniphila might be responsible for the efficacy of LBPW since decreasing the abundance of this bacterium by antibiotics (Abs) blocked the effectiveness of LBPW. Overall, our results show that LBPW may exert the hepatoprotective effect via rebalancing TGF-β/Smad7 signaling and propagating gut commensal A. muciniphila, suggesting that LBPW could be leading components to be developed as new drug candidates or nutraceuticals against liver fibrosis.
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Affiliation(s)
- Ying-Min Nie
- Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Wan-Qi Zhou
- Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- Lingang Laboratory, Shanghai, 201203, China
| | - Ting Niu
- Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Department of Pancreatic-biliary Surgery, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Meng-Fei Mao
- Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yu-Xue Zhan
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yun Li
- Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Kai-Ping Wang
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Mei-Xia Li
- Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Kan Ding
- Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
- Lingang Laboratory, Shanghai, 201203, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, SSIP Healthcare and Medicine Demonstration Zone, Zhongshan Tsuihang New District, Zhongshan, 528400, China.
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Villavicencio EA, Serdjebi C, Maldonado A, Ochoa Mora E, Besson A, Alkhouri N, Garcia DO. Use of Hepatoscope 2DTE for non-invasive assessment of liver stiffness among Mexican immigrant adults in a community-based setting. Clin Res Hepatol Gastroenterol 2025; 49:102581. [PMID: 40154879 DOI: 10.1016/j.clinre.2025.102581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 03/22/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025]
Abstract
PURPOSE Mexican-origin adults have one of the highest rates of metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe form metabolic dysfunction steatohepatitis (MASH) in the US. Given the costs and invasiveness of liver biopsy, this study assessed the application of Hepatoscope® 2DTE, the latest-generation transient elastography for liver stiffness in Mexican adult immigrants from Southern Arizona and compared it with FibroScan® VCTE™. METHODS Participants (n = 199) from a cross-sectional community-based study completed anthropometric measures, demographic information, a blood draw, and liver stiffness measurements (LSM) with FibroScan VCTE and the ultraportable Hepatoscope 2DTE. LSM2DTE and LSMVCTE were compared using Spearman's correlation and Bland-Altman analysis. The number of at-risk for fibrosis participants as assessed using each system was compared according to FIB-4. RESULTS A total of 122 participants were considered for this sub-analysis which consisted of 71.3 % women. Mean age was 51.9 ± 12.1 years, BMI was 30.7 ± 5.7 kg/m², 43.4 % of participants had obesity, and 19.7 % were diabetic. Mean FIB-4 was 1.00 ± 0.53, and median LSM were 5.6 [4.7 - 6.7] and 5.3 [4.1 - 5.8] kPa for 2DTE and VCTE, respectively. 2DTE significantly correlated with VCTE (r = 0.53, p < 0.0001) and there was no systematic bias between the two LSM. There was no difference in the number of at-risk for fibrosis participants between the two LSM per FIB-4 categories. CONCLUSION Hepatoscope can be used for point-of-care liver stiffness assessment and risk stratification of adults at risk of liver fibrosis in community-based settings.
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Affiliation(s)
- Edgar A Villavicencio
- University of Arizona, Mel and Enid Zuckerman College of Public Health, Health Promotion Sciences, Tucson, AZ, United States.
| | | | - Adriana Maldonado
- University of Arizona, Mel and Enid Zuckerman College of Public Health, Health Promotion Sciences, Tucson, AZ, United States
| | - Estefania Ochoa Mora
- University of Arizona, Clinical Translational Sciences, University of Arizona Health Sciences, Tucson, AZ, United States
| | | | | | - David O Garcia
- University of Arizona, Mel and Enid Zuckerman College of Public Health, Health Promotion Sciences, Tucson, AZ, United States
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Jian PA, Yang TN, Wang YX, Ma XY, Huang NN, Ren YF, Yuan SH, Li JL, Wang CC, Li XN. Lycopene, a natural plant extract, alleviates atrazine-induced ferroptosis in hepatocytes by activating cytochrome P450 oxidoreductase. Int J Biol Macromol 2025; 308:142311. [PMID: 40139611 DOI: 10.1016/j.ijbiomac.2025.142311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/16/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025]
Abstract
Atrazine (ATZ) and diaminochlorotriazine (DACT) accumulation poses liver health risks in animals and humans. Lycopene (LYC), a carotenoid found in red plants and fruits, exhibits potent antioxidant effects. This study explores the interaction between LYC and ATZ in mouse hepatocyte ferroptosis and the potential regulatory role of Cytochrome P450 oxidoreductase (CYPOR) in this process. Male mice were exposed to ATZ (50 mg/kg or 200 mg/kg) and/or LYC (5 mg/kg) by gavage for 21 days. In vitro experiments, a mouse hepatocyte cell line (AML12) was exposed to DACT (200 μM) and/or LYC (2 μM) for 12 h with or without small interfering RNA treatment. We found that both ATZ and DACT promoted CYPOR expression and caused liver injury. ATZ/DACT promotes Fe2+ accumulation and lipid peroxidation, ultimately leading to Ferroptosis in mouse hepatocytes. However, LYC alleviated ATZ/DACT-induced Ferroptosis by inhibiting CYPOR. The CYPOR knockdown resulted in the blockage of ATZ/DACT-induced ferroptosis, while the alleviation of ferroptosis by LYC was further enhanced. Thus, CYPOR can regulate ferroptosis in mouse hepatocytes and is a novel target for the treatment of hepatocyte ferroptosis-related diseases. Lycopene can be used as a functional dietary supplement to scavenge ferroptosis and reduce chronic liver disease.
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Affiliation(s)
- Ping-An Jian
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Tian-Ning Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yu-Xiang Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Xiang-Yu Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Ning-Ning Huang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yi-Fei Ren
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Shi-Hao Yuan
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China
| | - Chi-Chiu Wang
- Department of Obstetrics & Gynaecology, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, The Chinese University of Hong Kong-Sichuan University Joint Laboratory for Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong.
| | - Xue-Nan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China; Department of Obstetrics & Gynaecology, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, The Chinese University of Hong Kong-Sichuan University Joint Laboratory for Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin 150030, PR China.
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Pu Q, Xie K, Guo H, Zhu Y. Modeling crash avoidance behaviors in vehicle-pedestrian near-miss scenarios: Curvilinear time-to-collision and Mamba-driven deep reinforcement learning. ACCIDENT; ANALYSIS AND PREVENTION 2025; 214:107984. [PMID: 40043346 DOI: 10.1016/j.aap.2025.107984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/27/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025]
Abstract
Interactions between vehicle-pedestrian at intersections often lead to safety-critical situations. This study aims to model the crash avoidance behaviors of vehicles during interactions with pedestrians in near-miss scenarios, contributing to the development of collision avoidance systems and safety-aware traffic simulations. Unmanned aerial vehicles were leveraged to collect high-resolution trajectory data of vehicle-pedestrian at urban intersections. A new surrogate safety measure, curvilinear time-to-collision (CurvTTC), was employed to identify vehicle-pedestrian near-miss scenarios. CurvTTC takes into account the curved trajectories of road users instead of assuming straight-line future trajectories, making it particularly suitable for safety analysis at intersections, where turning vehicles usually follow curved paths. An effective algorithm considering predicted trajectories and collision types was designed to compute CurvTTC. When CurvTTC was applied to capture vehicle-pedestrian conflicts at intersections, it demonstrated superior performance in identifying risks more accurately compared to other surrogate safety measures, emphasizing the importance of considering the curved trajectories of road users. Further, a novel deep deterministic policy gradient based on the Mamba network (Mamba-DDPG) approach was used to model vehicles' crash avoidance behaviors during the vehicle-pedestrian conflicts captured. Results revealed that the Mamba-DDPG approach effectively learned the vehicle behaviors sequentially in both lateral and longitudinal dimensions during near-miss scenarios with pedestrians. The Mamba-DDPG approach achieved superior predictive accuracy by utilizing Mamba's dynamic data reweighting, which prioritizes critical states. This resulted in better performance compared to both the standard DDPG and the Transformer-enhanced DDPG (Transformer-DDPG) methods. The Mamba-DDPG approach was employed to reconstruct evasive trajectories of vehicles when approaching pedestrians and its effectiveness in capturing the underlying policy of crash avoidance behaviors was validated.
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Affiliation(s)
- Qingwen Pu
- Transportation Informatics Lab, Department of Civil and Environmental Engineering, Old Dominion University, Norfolk, VA 23529, United States
| | - Kun Xie
- Transportation Informatics Lab, Department of Civil and Environmental Engineering, Old Dominion University, Norfolk, VA 23529, United States.
| | - Hongyu Guo
- Data Analytics and Optimization, WSP, 12 Moorhouse Avenue, Addington, Christchurch 8011, New Zealand
| | - Yuan Zhu
- Inner Mongolia Center for Transportation Research, Inner Mongolia University, Rm A357A, Transportation Building, South Campus,49 S Xilin Rd, Hohhot, Inner Mongolia 010020, China
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Farzi M, McGenity C, Cratchley A, Leplat L, Bankhead P, Wright A, Treanor D. Liver-Quant: Feature-based image analysis toolkit for automatic quantification of metabolic dysfunction-associated steatotic liver disease. Comput Biol Med 2025; 190:110049. [PMID: 40121800 DOI: 10.1016/j.compbiomed.2025.110049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 02/26/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND Liver biopsy assessment by pathologists remains the gold standard for diagnosing metabolic dysfunction-associated steatotic liver disease (MASLD). Current automated image analysis tools for patient risk stratification are often proprietary or not applicable to whole slide images (WSIs). Here, we introduce "Liver-Quant," an open-source Python package for quantifying steatosis and fibrosis in liver WSIs. METHOD Liver-Quant leverages colour and morphological features to measure Steatosis Proportionate Area (SPA) and Collagen Proportionate Area (CPA). We evaluated the method using an internal dataset of 414 WSIs from adult patients (Leeds Teaching Hospitals NHS Trust, 2016-2022) and an external public dataset (109 WSIs). Semi-quantitative scores were extracted from pathological reports. The Spearman rank coefficient (ρ) assessed correlations between computed SPA/CPA and pathologist scores. RESULTS Steatosis quantification showed a substantial correlation (ρ = 0.92), while fibrosis quantification yielded a moderate correlation (ρ = 0.51). We further investigated the impact of three staining dyes (Van Gieson (VG), Picro Sirius Red (PSR), and Masson's Trichrome (MTC)) on fibrosis quantification (n = 18). Stain normalisation yielded excellent agreement in CPA measurements across all three stains. Without normalisation, PSR achieved the strongest correlation with human scores (ρ = 0.9) followed by VG (ρ = 0.8) and MTC (ρ = 0.59). Finally, we explored the impact of apparent magnification on SPA and CPA. High-resolution images (0.25 or 0.50 μm per pixel (MPP)) were necessary for accurate SPA measurement, while lower resolution (10 MPP) sufficed for CPA measurements. CONCLUSIONS Liver-Quant offers an open-source solution for rapid and precise MASLD quantification in WSIs applicable to multiple histological stains.
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Affiliation(s)
- Mohsen Farzi
- Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, UK; University of Leeds, Leeds, UK.
| | - Clare McGenity
- Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, UK; University of Leeds, Leeds, UK
| | - Alyn Cratchley
- Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Leo Leplat
- Centre for Genomic & Experimental Medicine, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Peter Bankhead
- Centre for Genomic & Experimental Medicine, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK; Edinburgh Pathology and CRUK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK
| | - Alexander Wright
- Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, UK; University of Leeds, Leeds, UK
| | - Darren Treanor
- Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, UK; University of Leeds, Leeds, UK; Department of Clinical Pathology & Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Centre for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden
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